Linear peptide antibiotics

ABSTRACT

Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. The compounds provided herein can in other embodiments overcome the resistance conferred by single amino acid mutations at defined positions of bacterial Signal Peptidases (SPases) and in other embodiments provide for a broad spectrum of antibiotic bioactivity. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.

CROSS-REFERENCE

This application claims the benefit of U.S. provisional application Ser.No. 61/730,928, filed Nov. 28, 2012, and U.S. provisional applicationSer. No. 61/599,851, filed Feb. 16, 2012; both of which are incorporatedby reference in their entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Jul. 28, 2014, isnamed 40681-702-201SEQ.txt and is 1,583 bytes in size.

BACKGROUND OF THE INVENTION

Since the appearance of the first antibiotic-resistant bacterial strainsin the 1940's, at least thirteen strains that are impervious to manyantibiotics have been discovered. According to the Infectious DiseaseSociety of America, bacteria that are resistant to one or more drugs areresponsible for some 100,000 U.S. hospital deaths a year, and cost thehealth care system more than $34 billion. The discovery of newantibiotics, especially those that act via the inhibition of a noveltarget, is an urgent need.

SUMMARY OF THE INVENTION

Described herein are linear peptides for the treatment of microbialinfections, such as for the treatment of bacterial infections. Invarious embodiments, the present disclosure provides lipopeptidecompounds for the treatment of bacterial infections. In variousembodiments, the lipopeptide compounds act by inhibition of bacterialtype 1 signal peptidase (SpsB), an essential protein in bacteria.

In one aspect described herein are compounds of Formula (I):

wherein:

-   -   R¹ is selected from:

-   -   R², R⁴, R¹⁰, R¹¹, R¹², and R¹³ are each independently —H, —CH₃,        —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH,        —CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂C(O)OR²⁵, —CH₂CH₂C(O)OH,        —CH₂CH₂C(O)OR²⁵, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,        —CH₂CH₂C(O)N(H)C(H)(CH₃)CO₂H, —CH₂CH₂C(O)N(H)C(H)(CO₂H)CH₂CO₂H,        —CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²², —(CH₂)₄NR²¹R²²,        —(CH₂)₄N(R²⁵)₃, —(CH₂)₄N(H)C(O)(2,3-dihydroxybenzene),        optionally substituted C₁-C₈alkyl, optionally substituted        C₁-C₈heteroalkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted —CH₂—C₃-C₈cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl,        optionally substituted heteroaryl,

-   -   R³ is methyl, ethyl, isopropyl, or cyclopropyl;    -   R⁵ is H, methyl, ethyl, or —CH₂OH; or R⁵ and R²⁴ together with        the boron atom form a 5- or 6-membered boron containing ring;    -   R⁶ is —C(═O)H, —CH₂C(═O)H, —C(═O)NHCH₂C(═O)H,        —C(═O)C(═O)N(R¹⁴)₂, —B(OR²³)(OR²⁴), or

or R⁵ and R⁶ together with the carbon atom form

-   -   R^(x) is H, optionally substituted C₁-C₆alkyl, optionally        substituted C₁-C₆heteroalkyl, or optionally substituted        C₃-C₈cycloalkyl; or R^(x) and R² together with the nitrogen atom        form an optionally substituted nitrogen containing ring;    -   R^(y) is H or methyl; or R^(y) and R⁵ together with the nitrogen        atom form an optionally substituted nitrogen containing ring;    -   R^(z) is —NR¹⁵R¹⁶, —CH₂—NR¹⁵R¹⁶, or —(CH₂)₂—NR¹⁵R¹⁶;    -   R⁷ is optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted heterocycloalkyl, optionally        substituted alkenyl, or a linear or branched alkyl chain of        about 1-22 carbon atoms, optionally comprising within the alkyl        chain or at an alkyl chain terminus an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted heterocycloalkyl, or an optionally substituted

wherein Z is a bond, O, S, NH, CH₂, NHCH₂, or C≡C;

-   -   R⁸ is a bond, —O—, or —N(R¹⁷)—, optionally substituted aryl, or        optionally substituted heteroaryl;    -   R⁹ is —CH₂OH, —CH₂CH(CH₃)₂,

-   -   R¹⁴, R¹⁵, and R¹⁶ are each independently H, or C₁-C₄alkyl;    -   R¹⁷ is H, methyl, ethyl, isopropyl, or cyclopropyl;    -   R¹⁸, R¹⁹, and R²⁰ are each independently H, or methyl;    -   each R²¹ is independently H, or C₁-C₄alkyl;    -   each R²² is independently H, C₁-C₄alkyl, —C(═NH)(NH₂), or        —CH(═NH);    -   R²³ and R²⁴ are each independently H, or C₁-C₄alkyl; or R²³ and        R²⁴ together with the boron atom form an optionally substituted        5- or 6-membered boron containing ring;    -   each R²⁵ is independently C₁-C₆alkyl;    -   R²⁶ is H, C₁-C₄alkyl, C₁-C₄alkoxy, —CH₂C(O)OR²⁵, or        —OCH₂C(O)OR²⁵;    -   n is 0 or 1;    -   p is 0 or 1; and    -   q is 0 or 1;    -   or a pharmaceutically acceptable salt, solvate, or prodrug        thereof.

In one embodiment is a compound of Formula (I) wherein R¹ is

In another embodiment is a compound of Formula (I) wherein R⁸ is a bond.In another embodiment is a compound of Formula (I) wherein R², R⁴, R¹⁰,R¹¹, R¹², and R¹³ are each independently —H, —CH₃, —CH(CH₃)₂, —C(CH₃)₃,—CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CF₃,—CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂,—(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂,

In another embodiment is a compound of Formula (I) wherein R², R⁴, R¹⁰,R¹¹, R¹², and R¹³ are each independently —H, —CH₃, —CH₂CH(CH₃)₂, —CH₂OH,—CH(OH)(CH₃), —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂,—(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂, or

In another embodiment is a compound of Formula (I) wherein n is 1 and pis 0.

In another embodiment is a compound of Formula (I) having the structureof Formula (Ib):

-   -   wherein R², R⁴, and R¹² are each independently —CH₂CH(CH₃)₂,        —(CH₂)₃NH₂, or —(CH₂)₄NH₂.

In another embodiment is a compound of Formula (I) wherein R¹ is

In a further embodiment is a compound of Formula (I) wherein R², R⁴,R¹², and R¹³ are each independently —H, —CH₃, —CH(CH₃)₂, —C(CH₃)₃,—CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CF₃,—CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂,—(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂,

In yet a further embodiment is a compound of Formula (I) wherein R², R⁴,R¹², and R¹³ are each independently —H, —CH₃, —CH₂CH(CH₃)₂, —CH₂OH,—CH(OH)(CH₃), —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂,—(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂,

In a further embodiment is a compound of Formula (I) wherein n is 0. Inyet a further embodiment is a compound of Formula (I) wherein R⁸ is abond.

In another embodiment is a compound of Formula (I) having the structureof Formula (Ic):

-   -   wherein R², R⁴, and R¹² are each independently —CH₂CH(CH₃)₂,        —CH(OH)(CH₃), —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂,        —(CH₂)₃NH₂, or —(CH₂)₄NH₂.

In another embodiment is a compound of Formula (I) wherein R¹ is

In a further embodiment is a compound of Formula (I) wherein R² and R⁴are each independently —H, —CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃),—CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂CH₂C(O)OH,—CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂,—(CH₂)₄NH₂,

In a further embodiment is a compound of Formula (I) wherein q is 1; andR⁸ is a bond.

In another embodiment is a compound of Formula (I) having the structureof Formula (Id):

-   -   wherein R^(z) is NH₂; and R² and R⁴ are each independently        —CH₂CH(CH₃)₂, —CH(OH)(CH₃), —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,        —CH₂NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂, or —(CH₂)₄NH₂.

In another aspect is a hydrate or metabolite of a compound of Formula(I).

In another aspect is a pharmaceutical composition comprising a compoundof Formula (I) and a pharmaceutically acceptable excipient.

In another aspect is the use of a compound of Formula (I) or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof, for the preparation of amedicament for the treatment of a bacterial infection in a patient.

In one aspect is a method for treating a bacterial infection in a mammalcomprising administering to the mammal a compound of Formula (I) or apharmaceutically acceptable salt or prodrug thereof at a frequency andfor a duration sufficient to provide a beneficial effect to the mammal.In another embodiment, the bacterial infection is an infection involvingPseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonasacidovorans, Pseudomonas alcaligenes, Pseudomonas putida,Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonashydrophilia, Escherichia coli, Citrobacter freundii, Salmonellatyphimurium, Salmonella typhi, Salmonella paratyphi, Salmonellaenteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei,Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae,Klebsiella oxytoca, Serratia marcescens, Francisella tularensis,Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providenciaalcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacterbaumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus,Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis,Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis,Bordetella bronchiseptica, Haemophilus influenzae, Haemophilusparainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus,Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica,Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus,Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibriocholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeriamonocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella,Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroidesdistasonis, Bacteroides 3452A homology group, Bacteroides vulgatus,Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis,Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile,Mycobacterium tuberculosis, Mycobacterium avium, Mycobacteriumintracellulare, Mycobacterium leprae, Corynebacterium diphtheriae,Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcusagalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcusfaecium, Staphylococcus aureus, Staphylococcus epidermidis,Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcushyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcushominis, or Staphylococcus saccharolyticus.

In another embodiment the bacterial infection is an infection involvinga Gram-negative bacteria. In another embodiment, administering comprisesa topical administration.

In a further embodiment are methods of treating a mammal in need of suchtreatment comprising administering to the mammal a second therapeuticagent. In another embodiment, the second therapeutic agent is not anSpsB inhibitor. In another embodiment, the second therapeutic agent isan aminoglycoside antibiotic, fluoroquinolone antibiotic, β-lactamantibiotic, macrolide antibiotic, glycopeptide antibiotic, rifampicin,chloramphenicol, fluoramphenicol, colistin, mupirocin, bacitracin,daptomycin, or linezolid. In another embodiment, the second therapeuticagent is a β-lactam antibiotic. In another embodiment, the β-lactamantibiotic is selected from penicillins, monobactams, cephalosporins,and carbapenems. A further embodiment comprises administeringβ-lactamase inhibitor.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise.

The term “about” as used herein, when referring to a numerical value orrange, allows for a degree of variability in the value or range, forexample, within 10%, or within 5% of a stated value or of a stated limitof a range.

All percent compositions are given as weight-percentages, unlessotherwise stated.

All average molecular weights of polymers are weight-average molecularweights, unless otherwise specified.

As used herein, “individual” (as in the subject of the treatment) meansboth mammals and non-mammals. Mammals include, for example, humans;non-human primates, e.g. apes and monkeys; and non-primates, e.g. dogs,cats, cattle, horses, sheep, and goats. Non-mammals include, forexample, fish and birds.

The term “disease” or “disorder” or “malcondition” are usedinterchangeably, and are used to refer to diseases or conditions whereina bacterial SPase plays a role in the biochemical mechanisms involved inthe disease or malcondition such that a therapeutically beneficialeffect can be achieved by acting on the enzyme. “Acting on” SPase caninclude binding to SPase and/or inhibiting the bioactivity of an SPase.

The expression “effective amount”, when used to describe therapy to anindividual suffering from a disorder, refers to the amount of a compounddescribed herein that is effective to inhibit or otherwise act on SPasein the individual's tissues wherein SPase involved in the disorder isactive, wherein such inhibition or other action occurs to an extentsufficient to produce a beneficial therapeutic effect.

“Substantially” as the term is used herein means completely or almostcompletely; for example, a composition that is “substantially free” of acomponent either has none of the component or contains such a traceamount that any relevant functional property of the composition isunaffected by the presence of the trace amount, or a compound is“substantially pure” is there are only negligible traces of impuritiespresent.

“Treating” or “treatment” within the meaning herein refers to analleviation of symptoms associated with a disorder or disease, orinhibition of further progression or worsening of those symptoms, orprevention or prophylaxis of the disease or disorder, or curing thedisease or disorder. Similarly, as used herein, an “effective amount” ora “therapeutically effective amount” of a compound refers to an amountof the compound that alleviates, in whole or in part, symptomsassociated with the disorder or condition, or halts or slows furtherprogression or worsening of those symptoms, or prevents or providesprophylaxis for the disorder or condition. In particular, a“therapeutically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredtherapeutic result. A therapeutically effective amount is also one inwhich any toxic or detrimental effects of compounds described herein areoutweighed by the therapeutically beneficial effects.

By “chemically feasible” is meant a bonding arrangement or a compoundwhere the generally understood rules of organic structure are notviolated; for example a structure within a definition of a claim thatwould contain in certain situations a pentavalent carbon atom that wouldnot exist in nature would be understood to not be within the claim. Thestructures disclosed herein, in all of their embodiments are intended toinclude only “chemically feasible” structures, and any recitedstructures that are not chemically feasible, for example in a structureshown with variable atoms or groups, are not intended to be disclosed orclaimed herein.

When a substituent is specified to be an atom or atoms of specifiedidentity, “or a bond”, a configuration is referred to when thesubstituent is “a bond” that the groups that are immediately adjacent tothe specified substituent are directly connected to each other in achemically feasible bonding configuration.

All chiral, diastereomeric, racemic forms of a structure are intended,unless a particular stereochemistry or isomeric form is specificallyindicated. Compounds described herein can include enriched or resolvedoptical isomers at any or all asymmetric atoms as are apparent from thedepictions, at any degree of enrichment. Both racemic and diastereomericmixtures, as well as the individual optical isomers can be isolated orsynthesized so as to be substantially free of their enantiomeric ordiastereomeric partners, and these are all within the scope of theinvention.

The inclusion of an isotopic form of one or more atoms in a moleculethat is different from the naturally occurring isotopic distribution ofthe atom in nature is referred to as an “isotopically labeled form” ofthe molecule. All isotopic forms of atoms are included as options in thecomposition of any molecule, unless a specific isotopic form of an atomis indicated. For example, any hydrogen atom or set thereof in amolecule can be any of the isotopic forms of hydrogen, i.e., protium(¹H), deuterium (²H), or tritium (³H) in any combination. Similarly, anycarbon atom or set thereof in a molecule can be any of the isotopic formof carbons, such as ¹¹C, ¹²C, ¹³C, or ¹⁴C, or any nitrogen atom or setthereof in a molecule can be any of the isotopic forms of nitrogen, suchas ¹³N, ¹⁴N, or ¹⁵N. A molecule can include any combination of isotopicforms in the component atoms making up the molecule, the isotopic formof every atom forming the molecule being independently selected. In amulti-molecular sample of a compound, not every individual moleculenecessarily has the same isotopic composition. For example, a sample ofa compound can include molecules containing various different isotopiccompositions, such as in a tritium or ¹⁴C radiolabeled sample where onlysome fraction of the set of molecules making up the macroscopic samplecontains a radioactive atom. It is also understood that many elementsthat are not artificially isotopically enriched themselves are mixturesof naturally occurring isotopic forms, such as ¹⁴N and ¹⁵N, ³²S and ³⁴S,and so forth. A molecule as recited herein is defined as includingisotopic forms of all its constituent elements at each position in themolecule. As is well known in the art, isotopically labeled compoundscan be prepared by the usual methods of chemical synthesis, exceptsubstituting an isotopically labeled precursor molecule. The isotopes,radiolabeled or stable, can be obtained by any method known in the art,such as generation by neutron absorption of a precursor nuclide in anuclear reactor, by cyclotron reactions, or by isotopic separation suchas by mass spectrometry. The isotopic forms are incorporated intoprecursors as required for use in any particular synthetic route. Forexample, ¹⁴C and ³H can be prepared using neutrons generated in anuclear reactor. Following nuclear transformation, ¹⁴C and ³H areincorporated into precursor molecules, followed by further elaborationas needed.

The term “amino protecting group” or “N-protected” as used herein refersto those groups intended to protect an amino group against undesirablereactions during synthetic procedures and which can later be removed toreveal the amine. Commonly used amino protecting groups are disclosed inProtective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M.,John Wiley & Sons, New York, N.Y., (3rd Edition, 1999). Amino protectinggroups include acyl groups such as formyl, acetyl, propionyl, pivaloyl,t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl,trichloroacetyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl,4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonylgroups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy-or aryloxy-carbonyl groups (which form urethanes with the protectedamine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl,isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl(Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl(Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyland the like; and silyl groups such as trimethylsilyl and the like.Amine protecting groups also include cyclic amino protecting groups suchas phthaloyl and dithiosuccinimidyl, which incorporate the aminonitrogen into a heterocycle. Typically, amino protecting groups includeformyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc,Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of theordinary artisan to select and use the appropriate amino protectinggroup for the synthetic task at hand.

The term “hydroxyl protecting group” or “O-protected” as used hereinrefers to those groups intended to protect an OH group againstundesirable reactions during synthetic procedures and which can later beremoved to reveal the amine. Commonly used hydroxyl protecting groupsare disclosed in Protective Groups in Organic Synthesis, Greene, T. W.;Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999).Hydroxyl protecting groups include acyl groups such as formyl, acetyl,propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl,trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, α-chlorobutyryl,benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like;sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like;acyloxy groups (which form urethanes with the protected amine) such asbenzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl,isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl(Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl(Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyland the like; and silyl groups such as trimethylsilyl and the like. Itis well within the skill of the ordinary artisan to select and use theappropriate hydroxyl protecting group for the synthetic task at hand.

In general, “substituted” refers to an organic group as defined hereinin which one or more bonds to a hydrogen atom contained therein arereplaced by one or more bonds to a non-hydrogen atom such as, but notlimited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groupssuch as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxygroups, oxo(carbonyl) groups, carboxyl groups including carboxylicacids, carboxylates, and carboxylate esters; a sulfur atom in groupssuch as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups,sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atomin groups such as amines, hydroxylamines, nitriles, nitro groups,N-oxides, hydrazides, azides, and enamines; and other heteroatoms invarious other groups. Non-limiting examples of substituents that can bebonded to a substituted carbon (or other) atom include F, Cl, Br, I,OR′, OC(O)N(R′)₂, CN, NO, NO₂, ONO₂, azido, CF₃, OCF₃, R′, O (oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R′)₂, SR′, SOR′,SO₂R′, SO₂N(R′)₂, SO₃R′, C(O)R′, C(O)C(O)R′, C(O)CH₂C(O)R′, C(S)R′,C(O)OR′, OC(O)R′, C(O)N(R′)₂, OC(O)N(R′)₂, C(S)N(R′)₂,(CH₂)₀₋₂N(R′)C(O)R′, (CH₂)₀₋₂N(R′)N(R′)₂, N(R′)N(R′)C(O)R′,N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′)₂, N(R′)SO₂R′, N(R′)SO₂N(R′)₂,N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)C(S)R′, N(R′)C(O)N(R′)₂,N(R′)C(S)N(R′)₂, N(COR′)COR′, N(OR′)R′, C(═NH)N(R′)₂, C(O)N(OR′)R′, orC(═NOR′)R′ wherein R′ can be hydrogen or a carbon-based moiety, andwherein the carbon-based moiety can itself be further substituted.

When a substituent is monovalent, such as, for example, F or Cl, it isbonded to the atom it is substituting by a single bond. When asubstituent is more than monovalent, such as O, which is divalent, itcan be bonded to the atom it is substituting by more than one bond,i.e., a divalent substituent is bonded by a double bond; for example, aC substituted with O forms a carbonyl group, C═O, which can also bewritten as “CO”, “C(O)”, or “C(═O)”, wherein the C and the O are doublebonded. When a carbon atom is substituted with a double-bonded oxygen(═O) group, the oxygen substituent is termed an “oxo” group. When adivalent substituent such as NR is double-bonded to a carbon atom, theresulting C(═NR) group is termed an “imino” group. When a divalentsubstituent such as S is double-bonded to a carbon atom, the resultsC(═S) group is termed a “thiocarbonyl” group.

Alternatively, a divalent substituent such as O, S, C(O), S(O), or S(O)₂can be connected by two single bonds to two different carbon atoms. Forexample, O, a divalent substituent, can be bonded to each of twoadjacent carbon atoms to provide an epoxide group, or the O can form abridging ether group, termed an “oxy” group, between adjacent ornon-adjacent carbon atoms, for example bridging the 1,4-carbons of acyclohexyl group to form a [2.2.1]-oxabicyclo system. Further, anysubstituent can be bonded to a carbon or other atom by a linker, such as(CH₂)_(n) or (CR′₂)_(n) wherein n is 1, 2, 3, or more, and each R′ isindependently selected.

C(O) and S(O)₂ groups can be bound to one or two heteroatoms, such asnitrogen, rather than to a carbon atom. For example, when a C(O) groupis bound to one carbon and one nitrogen atom, the resulting group iscalled an “amide” or “carboxamide.” When a C(O) group is bound to twonitrogen atoms, the functional group is termed a urea. When a S(O)₂group is bound to one carbon and one nitrogen atom, the resulting unitis termed a “sulfonamide.” When a S(O)₂ group is bound to two nitrogenatoms, the resulting unit is termed a “sulfamate.”

Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groupsas well as other substituted groups also include groups in which one ormore bonds to a hydrogen atom are replaced by one or more bonds,including double or triple bonds, to a carbon atom, or to a heteroatomsuch as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester,amide, imide, urethane, and urea groups; and nitrogen in imines,hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.

Substituted ring groups such as substituted cycloalkyl, aryl,heterocyclyl and heteroaryl groups also include rings and fused ringsystems in which a bond to a hydrogen atom is replaced with a bond to acarbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl andheteroaryl groups can also be substituted with alkyl, alkenyl, andalkynyl groups as defined herein.

By a “ring system” as the term is used herein is meant a moietycomprising one, two, three or more rings, which can be substituted withnon-ring groups or with other ring systems, or both, which can be fullysaturated, partially unsaturated, fully unsaturated, or aromatic, andwhen the ring system includes more than a single ring, the rings can befused, bridging, or spirocyclic. By “spirocyclic” is meant the class ofstructures wherein two rings are fused at a single tetrahedral carbonatom, as is well known in the art.

As to any of the groups described herein, which contain one or moresubstituents, it is understood, of course, that such groups do notcontain any substitution or substitution patterns which are stericallyimpractical and/or synthetically non-feasible. In addition, thecompounds of this disclosed subject matter include all stereochemicalisomers arising from the substitution of these compounds.

Selected substituents within the compounds described herein are presentto a recursive degree. In this context, “recursive substituent” meansthat a substituent may recite another instance of itself or of anothersubstituent that itself recites the first substituent. Because of therecursive nature of such substituents, theoretically, a large number maybe present in any given claim. One of ordinary skill in the art ofmedicinal chemistry and organic chemistry understands that the totalnumber of such substituents is reasonably limited by the desiredproperties of the compound intended. Such properties include, by ofexample and not limitation, physical properties such as molecularweight, solubility or log P, application properties such as activityagainst the intended target, and practical properties such as ease ofsynthesis.

Recursive substituents are an intended aspect of the disclosed subjectmatter. One of ordinary skill in the art of medicinal and organicchemistry understands the versatility of such substituents. To thedegree that recursive substituents are present in a claim of thedisclosed subject matter, the total number should be determined as setforth above.

The term “alkyl” refers to a straight or branched hydrocarbon chainradical group consisting solely of carbon and hydrogen atoms from 1 toabout 20 carbon atoms, and typically from 1 to 12 carbons or, in someembodiments, from 1 to 8 carbon atoms. Examples of straight chain alkylgroups include those with from 1 to 8 carbon atoms such as methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octylgroups. Examples of branched alkyl groups include, but are not limitedto, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompassesn-alkyl, isoalkyl, and anteisoalkyl groups as well as other branchedchain forms of alkyl. Representative substituted alkyl groups can besubstituted one or more times with any of the groups listed above, forexample, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, andhalogen groups. A description herein that a group is an alkyl chain“optionally comprising within the alkyl chain or at an alkyl chainterminus”, signifies that a moiety can be disposed between two subunitsof the alkyl chain, or can be disposed at an unsubstituted end of thechain, or can be disposed between the chain and a point of attachment ofthe chain, for example to a carbonyl, NR, or O group. For example, analkylbenzoyl group is an alkyl chain with a phenyl group disposedbetween the alkyl and a carbonyl, fitting the above description; anN-alkylphenylcarboxamido is an alkyl chain with a phenyl group disposedbetween the alkyl and the aminocarbonyl group, filling within the abovedescription.

The term “alkylene” means a linear saturated divalent hydrocarbonradical of one to six carbon atoms or a branched saturated divalenthydrocarbon radical of one to six carbon atoms unless otherwise stated,such as methylene, ethylene, propylene, 1-methylpropylene,2-methylpropylene, butylene, pentylene, and the like.

The term “carbonyl” means CO═O.

The terms “carboxy” and “hydroxycarbonyl” mean COOH.

Cycloalkyl groups are cyclic alkyl groups such as, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl groups. In some embodiments, the cycloalkyl group can have 3to about 8-12 ring members, whereas in other embodiments the number ofring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groupsfurther include polycyclic cycloalkyl groups such as, but not limitedto, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenylgroups, and fused rings such as, but not limited to, decalinyl, and thelike. Cycloalkyl groups also include rings that are substituted withstraight or branched chain alkyl groups as defined above. Representativesubstituted cycloalkyl groups can be mono-substituted or substitutedmore than once, such as, but not limited to, 2,2-, 2,3-, 2,4-2,5- or2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substitutednorbornyl or cycloheptyl groups, which can be substituted with, forexample, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, andhalogen groups. The term “cycloalkenyl” alone or in combination denotesa cyclic alkenyl group.

The terms “carbocyclic,” “carbocyclyl,” and “carbocycle” denote a ringstructure wherein the atoms of the ring are carbon, such as a cycloalkylgroup or an aryl group. In some embodiments, the carbocycle has 3 to 8ring members, whereas in other embodiments the number of ring carbonatoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary,the carbocyclic ring can be substituted with as many as N−1 substituentswherein N is the size of the carbocyclic ring with, for example, alkyl,alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl,heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groupsas are listed above. A carbocyclyl ring can be a cycloalkyl ring, acycloalkenyl ring, or an aryl ring. A carbocyclyl can be monocyclic orpolycyclic, and if polycyclic each ring can be independently be acycloalkyl ring, a cycloalkenyl ring, or an aryl ring.

(Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl groupsas defined above in which a hydrogen or carbon bond of the alkyl groupis replaced with a bond to a cycloalkyl group as defined above.

Alkenyl groups include straight and branched chain and cyclic alkylgroups as defined above, except that at least one double bond existsbetween two carbon atoms. Thus, alkenyl groups have from 2 to about 20carbon atoms, and typically from 2 to 12 carbons or, in someembodiments, from 2 to 8 carbon atoms. Examples include, but are notlimited to vinyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂,—C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, cyclohexenyl, cyclopentenyl,cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

Cycloalkenyl groups include cycloalkyl groups having at least one doublebond between 2 carbons. Thus for example, cycloalkenyl groups includebut are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienylgroups. Cycloalkenyl groups can have from 3 to about 8-12 ring members,whereas in other embodiments the number of ring carbon atoms range from3 to 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkylgroups such as, but not limited to, norbornyl, adamantyl, bornyl,camphenyl, isocamphenyl, and carenyl groups, and fused rings such as,but not limited to, decalinyl, and the like, provided they include atleast one double bond within a ring. Cycloalkenyl groups also includerings that are substituted with straight or branched chain alkyl groupsas defined above.

(Cycloalkenyl)alkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of the alkyl group is replaced with a bond to acycloalkenyl group as defined above.

Alkynyl groups include straight and branched chain alkyl groups, exceptthat at least one triple bond exists between two carbon atoms. Thus,alkynyl groups have from 2 to about 20 carbon atoms, and typically from2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.Examples include, but are not limited to —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃),—CH₂C≡CH, —CH₂C≡C(CH₃), and —CH₂C≡C(CH₂CH₃) among others.

The term “heteroalkyl” by itself or in combination with another termmeans, unless otherwise stated, a stable straight or branched chainalkyl group consisting of the stated number of carbon atoms and one ortwo heteroatoms selected from the group consisting of O, N, and S, andwherein the nitrogen and sulfur atoms may be optionally oxidized and thenitrogen heteroatom may be optionally quaternized. The heteroatom(s) maybe placed at any position of the heteroalkyl group, including betweenthe rest of the heteroalkyl group and the fragment to which it isattached, as well as attached to the most distal carbon atom in theheteroalkyl group. Examples include: —O—CH₂—CH₂—CH₃, —CH₂—CH₂CH₂—OH,—CH₂—CH₂—NH—CH₃, —CH₂—S—CH₂—CH₃, —CH₂CH₂—S(═O)—CH₃, and—CH₂CH₂—O—CH₂CH₂—O—CH₃. Up to two heteroatoms may be consecutive, suchas, for example, —CH₂—NH—OCH₃, or —CH₂—CH₂—S—S—CH₃.

A “cycloheteroalkyl” ring or “heterocycloalkyl” ring is a cycloalkylring containing at least one heteroatom. A cycloheteroalkyl ring canalso be termed a “heterocyclyl,” described below.

The term “heteroalkenyl” by itself or in combination with another termmeans, unless otherwise stated, a stable straight or branched chainmonounsaturated or di-unsaturated hydrocarbon group consisting of thestated number of carbon atoms and one or two heteroatoms selected fromthe group consisting of O, N, and S, and wherein the nitrogen and sulfuratoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quaternized. Up to two heteroatoms may be placedconsecutively. Examples include —CH═CH—O—CH₃, —CH═CH—CH₂—OH,—CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —CH₂—CH═CH—CH₂—SH, and—CH═CH—O—CH₂CH₂—O—CH₃.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms in the ring. Thus aryl groups include, but are not limitedto, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl,phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl,biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments,aryl groups contain about 6 to about 14 carbons in the ring portions ofthe groups. Aryl groups can be unsubstituted or substituted, as definedabove. Representative substituted aryl groups can be mono-substituted orsubstituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-,or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can besubstituted with carbon or non-carbon groups such as those listed above.

Aralkyl groups are alkyl groups as defined above in which a hydrogen orcarbon bond of an alkyl group is replaced with a bond to an aryl groupas defined above. Representative aralkyl groups include benzyl andphenylethyl groups and fused (cycloalkylaryl)alkyl groups such as4-ethyl-indanyl. Aralkenyl group are alkenyl groups as defined above inwhich a hydrogen or carbon bond of an alkyl group is replaced with abond to an aryl group as defined above.

Heterocyclyl groups or the term “heterocyclyl” includes aromatic andnon-aromatic ring compounds containing 3 or more ring members, of which,one or more is a heteroatom such as, but not limited to, N, O, and S.Thus a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or ifpolycyclic, any combination thereof. In some embodiments, heterocyclylgroups include 3 to about 20 ring members, whereas other such groupshave 3 to about 15 ring members. A heterocyclyl group designated as aC₂-heterocyclyl can be a 5-ring with two carbon atoms and threeheteroatoms, a 6-ring with two carbon atoms and four heteroatoms and soforth. Likewise a C₄-heterocyclyl can be a 5-ring with one heteroatom, a6-ring with two heteroatoms, and so forth. The number of carbon atomsplus the number of heteroatoms sums up to equal the total number of ringatoms. A heterocyclyl ring can also include one or more double bonds. Aheteroaryl ring is an embodiment of a heterocyclyl group. The phrase“heterocyclyl group” includes fused ring species including thosecomprising fused aromatic and non-aromatic groups. For example, adioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenylring system) are both heterocyclyl groups within the meaning herein. Thephrase also includes polycyclic ring systems containing a heteroatomsuch as, but not limited to, quinuclidyl. Heterocyclyl groups can beunsubstituted, or can be substituted as discussed above. Heterocyclylgroups include, but are not limited to, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl,benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl,indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl,thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinylgroups. Representative substituted heterocyclyl groups can bemono-substituted or substituted more than once, such as, but not limitedto, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or6-substituted, or disubstituted with groups such as those listed above.

Heteroaryl groups are aromatic ring compounds containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12ring members. A heteroaryl group is a variety of a heterocyclyl groupthat possesses an aromatic electronic structure. A heteroaryl groupdesignated as a C₂-heteroaryl can be a 5-ring with two carbon atoms andthree heteroatoms, a 6-ring with two carbon atoms and four heteroatomsand so forth. Likewise a C₄-heteroaryl can be a 5-ring with oneheteroatom, a 6-ring with two heteroatoms, and so forth. The number ofcarbon atoms plus the number of heteroatoms sums up to equal the totalnumber of ring atoms. Heteroaryl groups include, but are not limited to,groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl,benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroarylgroups can be unsubstituted, or can be substituted with groups as isdiscussed above. Representative substituted heteroaryl groups can besubstituted one or more times with groups such as those listed above.

Additional examples of aryl and heteroaryl groups include but are notlimited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl),N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl,anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl,isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl,acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl),imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl),triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl(1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl(2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl),3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl),5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl),7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl),benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl,5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl,5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Heterocyclylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group as defined above is replacedwith a bond to a heterocyclyl group as defined above. Representativeheterocyclyl alkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-ylethyl, and indol-2-yl propyl.

Heteroarylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheteroaryl group as defined above.

The term “alkoxy” refers to an oxygen atom connected to an alkyl group,including a cycloalkyl group, as are defined above. Examples of linearalkoxy groups include but are not limited to methoxy, ethoxy, propoxy,butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxyinclude but are not limited to isopropoxy, sec-butoxy, tert-butoxy,isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxyinclude but are not limited to cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can includeone to about 12-20 carbon atoms bonded to the oxygen atom, and canfurther include double or triple bonds, and can also includeheteroatoms. For example, an allyloxy group is an alkoxy group withinthe meaning herein. A methoxyethoxy group is also an alkoxy group withinthe meaning herein, as is a methylenedioxy group in a context where twoadjacent atoms of a structures are substituted therewith.

The term “thioalkoxy” refers to an alkyl group previously definedattached to the parent molecular moiety through a sulfur atom.

The term “glycosyloxyoxy” refers to a glycoside attached to the parentmolecular moiety through an oxygen atom.

The term “alkoxycarbonyl” represents as ester group; i.e. an alkoxygroup, attached to the parent molecular moiety through a carbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl, and the like.

The terms “halo” or “halogen” or “halide” by themselves or as part ofanother substituent mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom, preferably, fluorine, chlorine, or bromine.

A “haloalkyl” group includes mono-halo alkyl groups, poly-halo alkylgroups wherein all halo atoms can be the same or different, and per-haloalkyl groups, wherein all hydrogen atoms are replaced by halogen atoms,such as fluoro. Examples of haloalkyl include trifluoromethyl,1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl,perfluorobutyl, and the like.

A “haloalkoxy” group includes mono-halo alkoxy groups, poly-halo alkoxygroups wherein all halo atoms can be the same or different, and per-haloalkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms,such as fluoro. Examples of haloalkoxy include trifluoromethoxy,1,1-dichloroethoxy, 1,2-dichloroethoxy, 1,3-dibromo-3,3-difluoropropoxy,perfluorobutoxy, and the like.

The term “(C_(x)-C_(y))perfluoroalkyl,” wherein x<y, means an alkylgroup with a minimum of x carbon atoms and a maximum of y carbon atoms,wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is—(C₁-C₆)perfluoroalkyl, more preferred is —(C₁-C₃)perfluoroalkyl, mostpreferred is —CF₃.

The term “(C_(x)-C_(y))perfluoroalkylene,” wherein x<y, means an alkylgroup with a minimum of x carbon atoms and a maximum of y carbon atoms,wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is—(C₁-C₆)perfluoroalkylene, more preferred is —(C₁-C₃)perfluoroalkylene,most preferred is —CF₂—.

The terms “aryloxy” and “arylalkoxy” refer to, respectively, an arylgroup bonded to an oxygen atom and an aralkyl group bonded to the oxygenatom at the alkyl moiety. Examples include but are not limited tophenoxy, naphthyloxy, and benzyloxy.

An “acyl” group as the term is used herein refers to a group containinga carbonyl moiety wherein the group is bonded via the carbonyl carbonatom. The carbonyl carbon atom is also bonded to another carbon atom,which can be part of an alkyl, aryl, aralkyl cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl group or the like. In the special case wherein thecarbonyl carbon atom is bonded to a hydrogen, the group is a “formyl”group, an acyl group as the term is defined herein. An acyl group caninclude 0 to about 12-20 additional carbon atoms bonded to the carbonylgroup. An acyl group can include double or triple bonds within themeaning herein. An acryloyl group is an example of an acyl group. Anacyl group can also include heteroatoms within the meaning here. Anicotinoyl group (pyridyl-3-carbonyl) group is an example of an acylgroup within the meaning herein. Other examples include acetyl, benzoyl,phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and thelike. When the group containing the carbon atom that is bonded to thecarbonyl carbon atom contains a halogen, the group is termed a“haloacyl” group. An example is a trifluoroacetyl group.

The term “amine” includes primary, secondary, and tertiary amineshaving, e.g., the formula N(group)₃ wherein each group can independentlybe H or non-H, such as alkyl, aryl, and the like. Amines include but arenot limited to R—NH₂, for example, alkylamines, arylamines,alkylarylamines; R₂NH wherein each R is independently selected, such asdialkylamines, diarylamines, aralkylamines, heterocyclylamines and thelike; and R₃N wherein each R is independently selected, such astrialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, andthe like. The term “amine” also includes ammonium ions as used herein.

An “amino” group is a substituent of the form —NH₂, —NHR, —NR₂, —NR₃ ⁺,wherein each R is independently selected, and protonated forms of each,except for —NR₃ ⁺, which cannot be protonated. Accordingly, any compoundsubstituted with an amino group can be viewed as an amine. An “aminogroup” within the meaning herein can be a primary, secondary, tertiaryor quaternary amino group. An “alkylamino” group includes amonoalkylamino, dialkylamino, and trialkylamino group.

An “ammonium” ion includes the unsubstituted ammonium ion NH₄ ⁺, butunless otherwise specified, it also includes any protonated orquaternarized forms of amines. Thus, trimethylammonium hydrochloride andtetramethylammonium chloride are both ammonium ions, and amines, withinthe meaning herein.

The term “amide” (or “amido”) includes C- and N-amide groups, i.e.,—C(O)NR₂, and —NRC(O)R groups, respectively. Amide groups thereforeinclude but are not limited to primary carboxamide groups (—C(O)NH₂) andformamide groups (—NHC(O)H). A “carboxamido” or “aminocarbonyl” group isa group of the formula C(O)NR₂, wherein R can be H, alkyl, aryl, etc.

The term “azido” refers to an N₃ group. An “azide” can be an organicazide or can be a salt of the azide (N₃ ⁻) anion. The term “nitro”refers to an NO₂ group bonded to an organic moiety. The term “nitroso”refers to an NO group bonded to an organic moiety. The term nitraterefers to an ONO₂ group bonded to an organic moiety or to a salt of thenitrate (NO₃ ⁻) anion.

The term “urethane” (“carbamoyl” or “carbamyl”) includes N- andO-urethane groups, i.e., —NRC(O)OR and —OC(O)NR₂ groups, respectively.

The term “sulfonamide” (or “sulfonamido”) includes S- and N-sulfonamidegroups, i.e., —SO₂NR₂ and —NRSO₂R groups, respectively. Sulfonamidegroups therefore include but are not limited to sulfamoyl groups(—SO₂NH₂). An organosulfur structure represented by the formula—S(O)(NR)— is understood to refer to a sulfoximine, wherein both theoxygen and the nitrogen atoms are bonded to the sulfur atom, which isalso bonded to two carbon atoms.

The term “amidine” or “amidino” includes groups of the formula—C(NR)NR₂. Typically, an amidino group is —C(NH)NH₂.

The term “guanidine” or “guanidino” includes groups of the formula—NRC(NR)NR₂. Typically, a guanidino group is —NHC(NH)NH₂.

A “salt” as is well known in the art includes an organic compound suchas a carboxylic acid, a sulfonic acid, or an amine, in ionic form, incombination with a counterion. For example, acids in their anionic formcan form salts with cations such as metal cations, for example sodium,potassium, and the like; with ammonium salts such as NH₄ ⁺ or thecations of various amines, including tetraalkyl ammonium salts such astetramethylammonium, or other cations such as trimethylsulfonium, andthe like. A “pharmaceutically acceptable” or “pharmacologicallyacceptable” salt is a salt formed from an ion that has been approved forhuman consumption and is generally non-toxic, such as a chloride salt ora sodium salt. A “zwitterion” is an internal salt such as can be formedin a molecule that has at least two ionizable groups, one forming ananion and the other a cation, which serve to balance each other. Forexample, amino acids such as glycine can exist in a zwitterionic form. A“zwitterion” is a salt within the meaning herein. The compoundsdescribed herein may take the form of salts. The term “salts” embracesaddition salts of free acids or free bases which are compounds describedherein. Salts can be “pharmaceutically-acceptable salts.” The term“pharmaceutically-acceptable salt” refers to salts which possesstoxicity profiles within a range that affords utility in pharmaceuticalapplications. Pharmaceutically unacceptable salts may nonethelesspossess properties such as high crystallinity, which have utility in thepractice of the present disclosure, such as for example utility inprocess of synthesis, purification or formulation of compounds of thepresent disclosure.

Suitable pharmaceutically-acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric,salicylic, galactaric and galacturonic acid. Examples ofpharmaceutically unacceptable acid addition salts include, for example,perchlorates and tetrafluoroborates.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe present disclosure include, for example, metallic salts includingalkali metal, alkaline earth metal and transition metal salts such as,for example, calcium, magnesium, potassium, sodium and zinc salts.Pharmaceutically acceptable base addition salts also include organicsalts made from basic amines such as, for example,N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples ofpharmaceutically unacceptable base addition salts include lithium saltsand cyanate salts. Although pharmaceutically unacceptable salts are notgenerally useful as medicaments, such salts may be useful, for exampleas intermediates in the synthesis of Formula (I) compounds, for examplein their purification by recrystallization. All of these salts may beprepared by conventional means from the corresponding compound accordingto Formula (I) by reacting, for example, the appropriate acid or basewith the compound according to Formula (I). The term “pharmaceuticallyacceptable salts” refers to nontoxic inorganic or organic acid and/orbase addition salts, see, for example, Lit et al., Salt Selection forBasic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated byreference herein.

A “hydrate” is a compound that exists in a composition with watermolecules. The composition can include water in stoichiometicquantities, such as a monohydrate or a dihydrate, or can include waterin random amounts. As the term is used herein a “hydrate” refers to asolid form, i.e., a compound in water solution, while it may behydrated, is not a hydrate as the term is used herein.

A “solvate” is a similar composition except that a solvent other thatwater replaces the water. For example, methanol or ethanol can form an“alcoholate”, which can again be stoichiometic or non-stoichiometric. Asthe term is used herein a “solvate” refers to a solid form, i.e., acompound in solution in a solvent, while it may be solvated, is not asolvate as the term is used herein.

A “prodrug” as is well known in the art is a substance that can beadministered to a patient where the substance is converted in vivo bythe action of biochemicals within the patients body, such as enzymes, tothe active pharmaceutical ingredient. Examples of prodrugs includeesters of carboxylic acid groups, which can be hydrolyzed by endogenousesterases as are found in the bloodstream of humans and other mammals.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

In addition, where features or aspects of the present disclosure aredescribed in terms of Markush groups, those skilled in the art willrecognize that the presently described compounds is also therebydescribed in terms of any individual member or subgroup of members ofthe Markush group. For example, if X is described as selected from thegroup consisting of bromine, chlorine, and iodine, claims for X beingbromine and claims for X being bromine and chlorine are fully described.Moreover, where features or aspects of the present disclosure aredescribed in terms of Markush groups, those skilled in the art willrecognize that the present disclosure is also thereby described in termsof any combination of individual members or subgroups of members ofMarkush groups. Thus, for example, if X is described as selected fromthe group consisting of bromine, chlorine, and iodine, and Y isdescribed as selected from the group consisting of methyl, ethyl, andpropyl, claims for X being bromine and Y being methyl are fullydescribed.

If a value of a variable that is necessarily an integer, e.g., thenumber of carbon atoms in an alkyl group or the number of substituentson a ring, is described as a range, e.g., 0-4, what is meant is that thevalue can be any integer between 0 and 4 inclusive, i.e., 0, 1, 2, 3, or4.

In various embodiments, the compound or set of compounds, such as areused in the inventive methods, can be any one of any of the combinationsand/or sub-combinations of the above-listed embodiments.

In various embodiments, a compound as shown in any of the Examples, oramong the exemplary compounds, is provided. Provisos may apply to any ofthe disclosed categories or embodiments wherein any one or more of theother above disclosed embodiments or species may be excluded from suchcategories or embodiments.

The present disclosure further embraces isolated compounds according toFormula (I). The expression “isolated compound” refers to a preparationof a compound of Formula (I), or a mixture of compounds according toFormula (I), wherein the isolated compound has been separated from thereagents used, and/or byproducts formed, in the synthesis of thecompound or compounds. “Isolated” does not mean that the preparation istechnically pure (homogeneous), but it is sufficiently pure to compoundin a form in which it can be used therapeutically. Preferably an“isolated compound” refers to a preparation of a compound of Formula (I)or a mixture of compounds according to Formula (I), which contains thenamed compound or mixture of compounds according to Formula (I) in anamount of at least 10 percent by weight of the total weight. Preferablythe preparation contains the named compound or mixture of compounds inan amount of at least 50 percent by weight of the total weight; morepreferably at least 80 percent by weight of the total weight; and mostpreferably at least 90 percent, at least 95 percent or at least 98percent by weight of the total weight of the preparation.

The compounds described herein and intermediates may be isolated fromtheir reaction mixtures and purified by standard techniques such asfiltration, liquid-liquid extraction, solid phase extraction,distillation, recrystallization or chromatography, including flashcolumn chromatography, or HPLC.

Isomerism and Tautomerism in Compounds Described Herein

Tautomerism

Within the present disclosure it is to be understood that a compound ofthe Formula (I) or a salt thereof may exhibit the phenomenon oftautomerism whereby two chemical compounds that are capable of facileinterconversion by exchanging a hydrogen atom between two atoms, toeither of which it forms a covalent bond. Since the tautomeric compoundsexist in mobile equilibrium with each other they may be regarded asdifferent isomeric forms of the same compound. It is to be understoodthat the formulae drawings within this specification can represent onlyone of the possible tautomeric forms. However, it is also to beunderstood that the present disclosure encompasses any tautomeric form,and is not to be limited merely to any one tautomeric form utilizedwithin the formulae drawings. The formulae drawings within thisspecification can represent only one of the possible tautomeric formsand it is to be understood that the specification encompasses allpossible tautomeric forms of the compounds drawn not just those formswhich it has been convenient to show graphically herein. For example,tautomerism may be exhibited by a pyrazolyl group bonded as indicated bythe wavy line. While both substituents would be termed a 4-pyrazolylgroup, it is evident that a different nitrogen atom bears the hydrogenatom in each structure.

Such tautomerism can also occur with substituted pyrazoles such as3-methyl, 5-methyl, or 3,5-dimethylpyrazoles, and the like. Anotherexample of tautomerism is amido-imido (lactam-lactim when cyclic)tautomerism, such as is seen in heterocyclic compounds bearing a ringoxygen atom adjacent to a ring nitrogen atom. For example, theequilibrium:

is an example of tautomerism. Accordingly, a structure depicted hereinas one tautomer is intended to also include the other tautomer.Optical Isomerism

It will be understood that when compounds of the present disclosurecontain one or more chiral centers, the compounds may exist in, and maybe isolated as pure enantiomeric or diastereomeric forms or as racemicmixtures. The present disclosure therefore includes any possibleenantiomers, diastereomers, racemates or mixtures thereof of thecompounds described herein.

The isomers resulting from the presence of a chiral center comprise apair of non-superimposable isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active, i.e., they arecapable of rotating the plane of plane polarized light. Singleenantiomers are designated according to the Cahn-Ingold-Prelog system.The priority of substituents is ranked based on atomic weights, a higheratomic weight, as determined by the systematic procedure, having ahigher priority ranking. Once the priority ranking of the four groups isdetermined, the molecule is oriented so that the lowest ranking group ispointed away from the viewer. Then, if the descending rank order of theother groups proceeds clockwise, the molecule is designated (R) and ifthe descending rank of the other groups proceeds counterclockwise, themolecule is designated (S). In the example in Scheme 14, theCahn-Ingold-Prelog ranking is A>B>C>D. The lowest ranking atom, D isoriented away from the viewer.

The present disclosure is meant to encompass diastereomers as well astheir racemic and resolved, diastereomerically and enantiomerically pureforms and salts thereof. Diastereomeric pairs may be resolved by knownseparation techniques including normal and reverse phase chromatography,and crystallization.

“Isolated optical isomer” means a compound which has been substantiallypurified from the corresponding optical isomer(s) of the same formula.Preferably, the isolated isomer is at least about 80%, more preferablyat least 90% pure, even more preferably at least 98% pure, mostpreferably at least about 99% pure, by weight.

Isolated optical isomers may be purified from racemic mixtures bywell-known chiral separation techniques. According to one such method, aracemic mixture of a compound described herein, or a chiral intermediatethereof, is separated into 99% wt. % pure optical isomers by HPLC usinga suitable chiral column, such as a member of the series of DAICEL®CHIRALPAK® family of columns (Daicel Chemical Industries, Ltd., Tokyo,Japan). The column is operated according to the manufacturer'sinstructions.

Rotational Isomerism

It is understood that due to chemical properties (i.e., resonancelending some double bond character to the C—N bond) of restrictedrotation about the amide bond linkage (as illustrated below) it ispossible to observe separate rotamer species and even, under somecircumstances, to isolate such species (see below). It is furtherunderstood that certain structural elements, including steric bulk orsubstituents on the amide nitrogen, may enhance the stability of arotamer to the extent that a compound may be isolated as, and existindefinitely, as a single stable rotamer. The present disclosuretherefore includes any possible stable rotamers of Formula (I) which arebiologically active in the treatment of cancer or other proliferativedisease states.

Regioisomerism

In some embodiments, the compounds described herein have a particularspatial arrangement of substituents on the aromatic rings, which isrelated to the structure activity relationship demonstrated by thecompound class. Often such substitution arrangement is denoted by anumbering system; however, numbering systems are often not consistentbetween different ring systems. In six-membered aromatic systems, thespatial arrangements are specified by the common nomenclature “para” for1,4-substitution, “meta” for 1,3-substitution and “ortho” for1,2-substitution as shown below.

In various embodiments, the compound or set of compounds, such as areamong the inventive compounds or are used in the inventive methods, canbe any one of any of the combinations and/or sub-combinations of theabove-listed embodiments.

Compounds

In one aspect described herein are compounds of Formula (I):

wherein:

-   -   R¹ is selected from:

-   -   R², R⁴, R¹⁰, R¹¹, R¹², and R¹³ are each independently —H, —CH₃,        —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH,        —CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂C(O)OR²⁵, —CH₂CH₂C(O)OH,        —CH₂CH₂C(O)OR²⁵, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,        —CH₂CH₂C(O)N(H)C(H)(CH₃)CO₂H, —CH₂CH₂C(O)N(H)C(H)(CO₂H)CH₂CO₂H,        —CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²², —(CH₂)₄NR²¹R²²,        —(CH₂)₄N(R²⁵)₃, —(CH₂)₄N(H)C(O)(2,3-dihydroxybenzene),        optionally substituted C₁-C₈alkyl, optionally substituted        C₁-C₈heteroalkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted —CH₂—C₃-C₈cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl,        optionally substituted heteroaryl,

-   -   R³ is methyl, ethyl, isopropyl, or cyclopropyl;    -   R⁵ is H, methyl, ethyl, or —CH₂OH; or R⁵ and R²⁴ together with        the boron atom form a 5- or 6-membered boron containing ring;    -   R⁶ is —C(═O)H, —CH₂C(═O)H, —C(═O)NHCH₂C(═O)H,        —C(═O)C(═O)N(R¹⁴)₂, —B(OR²³)(OR²⁴), or

or R⁵ and R⁶ together with the carbon atom form

-   -   R^(x) is H, optionally substituted C₁-C₆alkyl, optionally        substituted C₁-C₆heteroalkyl, or optionally substituted        C₃-C₈cycloalkyl; or R^(x) and R² together with the nitrogen atom        form an optionally substituted nitrogen containing ring;    -   R^(y) is H or methyl; or R^(y) and R⁵ together with the nitrogen        atom form an optionally substituted nitrogen containing ring;    -   R^(z) is —NR¹⁵R¹⁶, —CH₂—NR¹⁵R¹⁶, or —(CH₂)₂—NR¹⁵R¹⁶;    -   R⁷ is optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted heterocycloalkyl, optionally        substituted alkenyl, or a linear or branched alkyl chain of        about 1-22 carbon atoms, optionally comprising within the alkyl        chain or at an alkyl chain terminus an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted heterocycloalkyl, or an optionally substituted

wherein Z is a bond, O, S, NH, CH₂, NHCH₂, or C≡C;

-   -   R⁸ is a bond, —O—, or —N(R¹⁷)—, optionally substituted aryl, or        optionally substituted heteroaryl;    -   R⁹ is —CH₂OH, —CH₂CH(CH₃)₂,

-   -   R¹⁴, R¹⁵, and R¹⁶ are each independently H, or C₁-C₄alkyl;    -   R¹⁷ is H, methyl, ethyl, isopropyl, or cyclopropyl;    -   R¹⁸, R¹⁹, and R²⁰ are each independently H, or methyl;    -   each R²¹ is independently H, or C₁-C₄alkyl;    -   each R²² is independently H, C₁-C₄alkyl, —C(═NH)(NH₂), or        —CH(═NH);    -   R²³ and R²⁴ are each independently H, or C₁-C₄alkyl; or R²³ and        R²⁴ together with the boron atom form an optionally substituted        5- or 6-membered boron containing ring;    -   each R²⁵ is independently C₁-C₆alkyl;    -   R²⁶ is H, C₁-C₄alkyl, C₁-C₄alkoxy, —CH₂C(O)OR²⁵, or        —OCH₂C(O)OR²⁵;    -   n is 0 or 1;    -   p is 0 or 1; and    -   q is 0 or 1;    -   or a pharmaceutically acceptable salt, solvate, or prodrug        thereof.

In one embodiment is a compound of Formula (I) having the structure ofFormula (I′):

wherein:

-   -   R¹ is selected from:

-   -   R², R⁴, R¹⁰, R¹¹, R¹², and R¹³ are each independently —H, —CH₃,        —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH,        —CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂C(O)OR²⁵, —CH₂CH₂C(O)OH,        —CH₂CH₂C(O)OR²⁵, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,        —CH₂CH₂C(O)N(H)C(H)(CH₃)CO₂H, —CH₂CH₂C(O)N(H)C(H)(CO₂H)CH₂CO₂H,        —CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²², —(CH₂)₄NR²¹R²²,        —(CH₂)₄N(R²⁵)₃, —(CH₂)₄N(H)C(O)(2,3-dihydroxybenzene),        optionally substituted C₁-C₈alkyl, optionally substituted        C₁-C₈heteroalkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted —CH₂—C₃-C₈cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl,        optionally substituted heteroaryl,

-   -   R³ is methyl, ethyl, isopropyl, or cyclopropyl;    -   R⁵ is H, methyl, ethyl, or —CH₂OH; or R⁵ and R²⁴ together with        the boron atom form a 5- or 6-membered boron containing ring;    -   R⁶ is —C(═O)H, —CH₂C(═O)H, —C(═O)NHCH₂C(═O)H,        —C(═O)C(═O)N(R¹⁴)₂, —B(OR²³)(OR²⁴), or

or R⁵ and R⁶ together with the carbon atom form

-   -   R^(x) is H, optionally substituted C₁-C₆alkyl, optionally        substituted C₁-C₆heteroalkyl, or optionally substituted        C₃-C₈cycloalkyl; or R^(x) and R² together with the nitrogen atom        form an optionally substituted nitrogen containing ring;    -   R^(y) is H or methyl; or R^(y) and R⁵ together with the nitrogen        atom form an optionally substituted nitrogen containing ring;    -   R^(z) is —NR¹⁵R¹⁶, —CH₂—NR¹⁵R¹⁶, or —(CH₂)₂—NR¹⁵R¹⁶;    -   R⁷ is optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted heterocycloalkyl, optionally        substituted alkenyl, or a linear or branched alkyl chain of        about 1-22 carbon atoms, optionally comprising within the alkyl        chain or at an alkyl chain terminus an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted heterocycloalkyl, or an optionally substituted

wherein Z is a bond, O, S, NH, CH₂, NHCH₂, or C≡C;

-   -   R⁸ is a bond, —O—, or —N(R¹⁷)—, optionally substituted aryl, or        optionally substituted heteroaryl;    -   R⁹ is —CH₂OH, —CH₂CH(CH₃)₂,

-   -   R¹⁴, R¹⁵, and R¹⁶ are each independently H, or C₁-C₄alkyl;    -   R¹⁷ is H, methyl, ethyl, isopropyl, or cyclopropyl;    -   R¹⁸, R¹⁹, and R²⁰ are each independently H, or methyl;    -   each R²¹ is independently H, or C₁-C₄alkyl;    -   each R²² is independently H, C₁-C₄alkyl, —C(═NH)(NH₂), or        —CH(═NH);    -   R²³ and R²⁴ are each independently H, or C₁-C₄alkyl; or R²³ and        R²⁴ together with the boron atom form an optionally substituted        5- or 6-membered boron containing ring;    -   each R²⁵ is independently C₁-C₆alkyl;    -   R²⁶ is H, C₁-C₄alkyl, C₁-C₄alkoxy, —CH₂C(O)OR²⁵, or        —OCH₂C(O)OR²⁵;    -   n is 0 or 1;    -   p is 0 or 1; and    -   q is 0 or 1;    -   or a pharmaceutically acceptable salt, solvate, or prodrug        thereof.

In one embodiment is a compound of Formula (I) or Formula (I′) whereinR¹ is

In a further embodiment, R⁸ is a bond. In another embodiment, R², R⁴,R¹⁰, R¹¹, R¹², and R¹³ are each independently —H, —CH₃, —CH(CH₃)₂,—C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CF₃,—CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —(CH₂)₂NH₂,—(CH₂)₃NH₂, —(CH₂)₄NH₂,

In a further embodiment, R², R⁴, R¹⁰, R¹¹, R¹², and R¹³ are eachindependently —H, —CH₃, —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂,—CH₂OH, —CH(OH)(CH₃), —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,—(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂,

In yet a further embodiment, R², R⁴, R¹⁰, R¹¹, R¹², and R¹³ are eachindependently —H, —CH₃, —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃),—CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂,—(CH₂)₄NH₂,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) or Formula (I′) wherein n is 0 and p is 0. In anotherembodiment, n is 0 and p is 1. In yet a further embodiment, n is 1 and pis 0.

-   -   In a further embodiment is a compound of Formula (I′) having the        structure of Formula (Ia):

In another embodiment is a compound of Formula (Ia) wherein R² is—CH(OH)(CH₃), —CH₂CH₂C(O)OH, or —(CH₂)₄NH₂. In some embodiments, R² is—CH(OH)(CH₃). In some embodiments, R² is —CH₂CH₂C(O)OH. In someembodiments, R² is —(CH₂)₄NH₂. In a further embodiment is a compound ofFormula (Ia) wherein R⁴ is CH₂CH(CH₃)₂ or —CH₂C(O)NH₂. In someembodiments, R⁴ is CH₂CH(CH₃)₂. In some embodiments, R⁴ is —CH₂C(O)NH₂.In yet a further embodiment is a compound of Formula (Ia) wherein R⁵ isH or —CH₃. In some embodiments, R⁴ is H. In some embodiments, R⁴ is—CH₃.

In another embodiment is a compound of Formula (I) or Formula (I′)wherein R¹ is

In a further embodiment, R⁸ is a bond. In another embodiment, R², R⁴,R¹⁰, R¹¹, R¹², and R¹³ are each independently —H, —CH₃, —CH(CH₃)₂,—C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CF₃,—CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂,—(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂,

In a further embodiment, R², R⁴, R¹⁰, R¹¹, R¹², and R¹³ are eachindependently —H, —CH₃, —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂,—CH₂OH, —CH(OH)(CH₃), —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,—(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)NH₂,

In yet a further embodiment, R², R⁴, R¹⁰, R¹¹, R¹², and R¹³ are eachindependently —H, —CH₃, —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃),—CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂,—(CH₂)₃NH₂, —(CH₂)₄NH₂, or

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) or Formula (I′) wherein n is 0 and p is 0. In anotherembodiment, n is 0 and p is 1. In yet a further embodiment, n is 1 and pis 0.

In a further embodiment is a compound of Formula (I′) having thestructure of Formula (Ib):

-   -   wherein R², R⁴, and R¹², are each independently —CH₂CH(CH₃)₂,        —(CH₂)₃NH₂, or —(CH₂)₄NH₂.

In another embodiment is a compound of Formula (Ib) wherein R², R⁴, andR¹² are each —(CH₂)₄NH₂. In another embodiment is a compound of Formula(Ib) wherein R², R⁴, and R¹² are each —(CH₂)₃NH₂. In another embodimentis a compound of Formula (Ib) wherein R⁴ is —CH₂CH(CH₃)₂, R² is—(CH₂)₃NH₂, and R¹² is —(CH₂)₄NH₂. In another embodiment is a compoundof Formula (Ib) wherein R⁴ is —CH₂CH(CH₃)₂, R² is —(CH₂)₄NH₂, and R¹² is—(CH₂)₄NH₂.

In a further embodiment is a compound of Formula (I′) having thestructure of Formula (Ibb):

-   -   wherein R⁵ is —H, or —CH₃.

In a further embodiment is a compound of Formula (I′) having thestructure of Formula (Ibbb):

-   -   wherein R⁵ is —H, or —CH₃.

In another embodiment is a compound of Formula (I) or Formula (I′)wherein R¹ is

In a further embodiment, R⁸ is a bond. In another embodiment, R², R⁴,R¹², and R¹³ are each independently —H, —CH₃, —CH(CH₃)₂, —C(CH₃)₃,—CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CF₃,—CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂,—(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂,

In a further embodiment, R², R⁴, R¹², and R¹³ are each independently —H,—CH₃, —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃),—CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂,—(CH₂)₃NH₂, —(CH₂)₄NH₂,

In yet a further embodiment, R², R⁴, R¹², and R¹³ are each independently—H, —CH₃, —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CH₂C(O)OH,—CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂,—(CH₂)₄NH₂,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) or Formula (I′) wherein n is 0. In yet a furtherembodiment, n is 1.

In a further embodiment is a compound of Formula (I′) having thestructure of Formula (Ic):

-   -   wherein R², R⁴, and R¹², are each independently —CH₂CH(CH₃)₂,        —CH(OH)(CH₃), —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂,        —(CH₂)₃NH₂, or —(CH₂)₄NH₂.

In another embodiment is a compound of Formula (Ic) wherein R⁴ is—(CH₂)₄NH₂, R² is —CH(OH)(CH₃), and R¹² is —(CH₂)₂NH₂. In anotherembodiment is a compound of Formula (Ic) wherein R⁴ is —(CH₂)₄NH₂, R² is—CH(OH)(CH₃), and R¹² is —CH₂NH₂. In another embodiment is a compound ofFormula (Ic) wherein R⁴ is —CH₂C(O)NH₂, R² is —CH(OH)(CH₃), and R¹² is—(CH₂)₄NH₂. In another embodiment is a compound of Formula (Ic) whereinR⁴ is —(CH₂)₄NH₂, R² is —(CH₂)₄NH₂, and R¹² is —CH₂NH₂. In anotherembodiment is a compound of Formula (Ic) wherein R⁴ is —CH₂C(O)NH₂, R²is —(CH₂)₄NH₂, and R¹² is —CH₂NH₂. In another embodiment is a compoundof Formula (Ic) wherein R⁴ is —CH₂CH(CH₃)₂, R² is —(CH₂)₂NH₂, and R¹² is—(CH₂)₂NH₂.

In a further embodiment is a compound of Formula (I′) having thestructure of Formula (Icc):

-   -   wherein R⁵ is —H, or —CH₃.

In another embodiment is a compound of Formula (I) or Formula (I′)wherein R¹ is

In a further embodiment, R² and R⁴ are each independently —H, —CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH,—CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂,—CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂,

In a further embodiment, q is 1 and R⁸ is a bond.

In a further embodiment is a compound of Formula (I′) having thestructure of Formula (Id):

-   -   wherein R^(z) is NH₂; and R² and R⁴ are each independently        —CH₂CH(CH₃)₂, —CH(OH)(CH₃), —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,        —CH₂NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂, or —(CH₂)₄NH₂.

In another embodiment is a compound of Formula (Id) wherein R² is—CH(OH)(CH₃), and R⁴ is —CH₂C(O)NH₂. In another embodiment is a compoundof Formula (Id) wherein R² is —CH(OH)(CH₃), and R⁴ is —(CH₂)₂NH₂. Inanother embodiment is a compound of Formula (Id) wherein R² is—CH(OH)(CH₃), and R⁴ is —(CH₂)₃NH₂. In another embodiment is a compoundof Formula (Id) wherein R² is —CH(OH)(CH₃), and R⁴ is —(CH₂)₄NH₂. Inanother embodiment is a compound of Formula (Id) wherein R² is—(CH₂)₄NH₂ and R⁴ is —CH₂CH(CH₃)₂. In another embodiment is a compoundof Formula (Id) wherein R² is —(CH₂)₄NH₂ and R⁴ is —CH₂C(O)NH₂. Inanother embodiment is a compound of Formula (Id) wherein R² is—(CH₂)₄NH₂ and R⁴ is —(CH₂)₄NH₂.

In another embodiment is a compound of Formula (I) or Formula (I′)wherein R¹ is

In a further embodiment, R⁸ is a bond. In another embodiment, R², R⁴,R¹⁰, R¹², and R¹³ are each independently —H, —CH₃, —CH(CH₃)₂, —C(CH₃)₃,—CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CF₃,—CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —(CH₂)₂NH₂,—(CH₂)₃NH₂, —(CH₂)₄NH₂,

In a further embodiment, R², R⁴, R¹⁰, R¹², and R¹³ are eachindependently —H, —CH₃, —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂,—CH₂OH, —CH(OH)(CH₃), —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,—(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂,

In yet a further embodiment, R², R⁴, R¹⁰, R¹², and R¹³ are eachindependently —H, —CH₃, —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃),—CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂,—(CH₂)₄NH₂,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) or Formula (I′) wherein n is 0. In yet a furtherembodiment, n is 1.

In a further embodiment is a compound of Formula (I′) having thestructure of Formula (Idd):

-   -   wherein R⁵ is —H, or —CH₃.

In another embodiment is a compound of Formula (Idd) wherein R¹⁰ is—CH₂OH, and R¹² is —CH₃. In another embodiment is a compound of Formula(Idd) wherein R¹⁰ is —CH₂CH(CH₃)₂, and R¹² is —CH(OH)(CH₃). In anotherembodiment of the aforementioned compounds of Formula (Id) is a compoundwherein R⁴ is —CH₂C(O)NH₂. In yet another embodiment of theaforementioned compounds of Formula (Idd) is a compound wherein R⁴ is

In another embodiment is a compound of Formula (I) or Formula (I′)wherein R¹ is

In a further embodiment, R⁸ is a bond. In another embodiment, R², R⁴,R¹², and R¹³ are each independently —H, —CH₃, —CH(CH₃)₂, —C(CH₃)₃,—CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CF₃,—CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂,—(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂,

In a further embodiment, R², R⁴, R¹², and R¹³ are each independently —H,—CH₃, —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃),—CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂,—(CH₂)₃NH₂, —(CH₂)₄NH₂,

In yet a further embodiment, R², R⁴, R¹², and R¹³ are each independently—H, —CH₃, —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CH₂C(O)OH,—CH₂C(O)NH₂, —CH₂NH₂, —CH₂CH₂C(O)NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂,—(CH₂)₄NH₂,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) or Formula (I′) wherein n is 0. In yet a furtherembodiment, n is 1.

In another embodiment is a compound of Formula (I) or Formula (I′)wherein R¹ is

In a further embodiment, R⁸ is a bond. In another embodiment, R² and R⁴are each independently —H, —CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃),—CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂CH₂C(O)OH,—CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂,

In a further embodiment, R² and R⁴ are each independently —H, —CH₃,—CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃),—CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂,—(CH₂)₄NH₂,

In yet a further embodiment, R² and R⁴ are each independently —H, —CH₃,—CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CH₂C(O)OH, —CH₂C(O)NH₂,—CH₂CH₂C(O)NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂,

In another embodiment is a compound of Formula (I) or Formula (I′)wherein R^(x) and R² together with the nitrogen atom form an optionallysubstituted nitrogen containing ring. In a further embodiment is acompound of Formula (I′) having the structure of Formula (Ie):

-   -   wherein R⁵ is —H, or —CH₃.

In another embodiment is a compound of Formula (Ie) wherein R¹⁶ and R¹²are each independently —H, —CH₃, —CH₂CH(CH₃)₂, —CH₂OH, or —CH(OH)(CH₃).

In another embodiment of any of the aforementioned embodiments ofFormula (I) or Formula (I′) is a compound wherein R⁶ is —C(═O)H.

In another aspect described herein are compounds of Formula (II):

wherein:

-   -   R², R⁴, and R¹² are each independently —H, —CH₃, —CH(CH₃)₂,        —C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃),        —CH₂CF₃, —CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,        —CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²², —(CH₂)₄NR²¹R²²,        optionally substituted C₁-C₈alkyl, optionally substituted        C₁-C₈heteroalkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted —CH₂—C₃-C₈cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl,        optionally substituted heteroaryl,

-   -   R³ is methyl, ethyl, isopropyl, or cyclopropyl;    -   R⁵ is H, methyl, ethyl, or —CH₂OH; or R⁵ and R²⁴ together with        the boron atom form a 5- or 6-membered boron containing ring;    -   R⁶ is —CH₂C(═O)H, —C(═O)NHCH₂C(═O)H, —C(═O)C(═O)N(R¹⁴)₂,        —B(OR²³)(OR²⁴), or

-   -   R^(x) is H, optionally substituted C₁-C₆alkyl, optionally        substituted C₁-C₆heteroalkyl, or optionally substituted        C₃-C₈cycloalkyl; or IV and R² together with the nitrogen atom        form an optionally substituted nitrogen containing ring;    -   R^(y) is H or methyl; or R^(y) and R⁵ together with the nitrogen        atom form an optionally substituted nitrogen containing ring;    -   R⁷ is optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted heterocycloalkyl, optionally        substituted alkenyl, or a linear or branched alkyl chain of        about 1-22 carbon atoms, optionally comprising within the alkyl        chain or at an alkyl chain terminus an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted heterocycloalkyl, or an optionally substituted

wherein Z is a bond, O, S, NH, CH₂, NHCH₂, or C≡C;

-   -   R⁸ is bond, optionally substituted aryl, optionally substituted        heteroaryl, or optionally substituted heterocycloalkyl;    -   R¹⁴ is each independently H, or C₁-C₄alkyl;    -   each R²¹ is independently H, or C₁-C₄alkyl;    -   each R²² is independently H, C₁-C₄alkyl, —C(═NH)(NH₂), or        —CH(═NH);    -   R²³ and R²⁴ are each independently H, or C₁-C₄alkyl; or R²³ and        R²⁴ together with the boron atom form an optionally substituted        5- or 6-membered boron containing ring; and    -   m is 0-4;    -   or a pharmaceutically acceptable salt, solvate, or prodrug        thereof.

In another embodiment is a compound of Formula (II) having the structureof Formula (II′):

wherein:

-   -   R², R⁴, and R¹² are each independently —H, —CH₃, —CH(CH₃)₂,        —C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃),        —CH₂CF₃, —CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,        —CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²², —(CH₂)₄NR²¹R²²,        optionally substituted C₁-C₈alkyl, optionally substituted        C₁-C₈heteroalkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted —CH₂—C₃-C₈cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl,        optionally substituted heteroaryl,

-   -   R³ is methyl, ethyl, isopropyl, or cyclopropyl;    -   R⁵ is H, methyl, ethyl, or —CH₂OH; or R⁵ and R²⁴ together with        the boron atom form a 5- or 6-membered boron containing ring;    -   R⁶ is —CH₂C(═O)H, —C(═O)NHCH₂C(═O)H, —C(═O)C(═O)N(R¹⁴)₂,        —B(OR²³)(OR²⁴), or

-   -   R^(x) is H, optionally substituted C₁-C₆alkyl, optionally        substituted C₁-C₆heteroalkyl, or optionally substituted        C₃-C₈cycloalkyl; or R^(x) and R² together with the nitrogen atom        form an optionally substituted nitrogen containing ring;    -   R^(y) is H or methyl; or R^(y) and R⁵ together with the nitrogen        atom form an optionally substituted nitrogen containing ring;    -   R⁷ is optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted heterocycloalkyl, optionally        substituted alkenyl, or a linear or branched alkyl chain of        about 1-22 carbon atoms, optionally comprising within the alkyl        chain or at an alkyl chain terminus an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted heterocycloalkyl, or an optionally substituted

wherein Z is a bond, O, S, NH, CH₂, NHCH₂, or C≡C;

-   -   R⁸ is bond, optionally substituted aryl, optionally substituted        heteroaryl, or optionally substituted heterocycloalkyl;    -   R¹⁴ is each independently H, or C₁-C₄alkyl;    -   each R²¹ is independently H, or C₁-C₄alkyl;    -   each R²² is independently H, C₁-C₄alkyl, —C(═NH)(NH₂), or        —CH(═NH);    -   R²³ and R²⁴ are each independently H, or C₁-C₄alkyl; or R²³ and        R²⁴ together with the boron atom form an optionally substituted        5- or 6-membered boron containing ring; and    -   m is 0-4;    -   or a pharmaceutically acceptable salt, solvate, or prodrug        thereof.

In a further embodiment is a compound of Formula (II) or Formula (II′)wherein R⁸ is a bond. In another embodiment of Formula (II) or Formula(II′), R² and R⁴ are each independently —H, —CH₃, —CH(CH₃)₂, —C(CH₃)₃,—CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CF₃,—CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —(CH₂)₂NH₂,—(CH₂)₃NH₂, —(CH₂)₄NH₂,

In a further embodiment, R² and R⁴ are each independently —H, —CH₃,—CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃),—CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂,—(CH₂)₄NH₂,

In yet a further embodiment, R² and R⁴ are each independently —H, —CH₃,—CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CH₂C(O)OH, —CH₂C(O)NH₂,—CH₂CH₂C(O)NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂,

In another aspect described herein are compounds of Formula (III):

wherein:

-   -   R² and R⁴ are each independently —H, —CH₃, —CH(CH₃)₂, —C(CH₃)₃,        —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CF₃,        —CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,        —CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²², —(CH₂)₄NR²¹R²²,        optionally substituted C₁-C₈alkyl, optionally substituted        C₁-C₈heteroalkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted —CH₂—C₃-C₈cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl,        optionally substituted heteroaryl,

-   -   R¹² and R¹³ are each independently —H, —NR²¹R²², —CH₃,        —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH,        —CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂,        —CH₂CH₂C(O)NH₂, —CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²²,        —(CH₂)₄NR²¹R²², optionally substituted C₁-C₈alkyl, or optionally        substituted C₁-C₈heteroalkyl; or R¹² and R¹³ together with the        carbon atoms to which they are attached form a heterocycloalkyl        ring;    -   R³ is methyl, ethyl, isopropyl, or cyclopropyl;    -   R⁵ is H, methyl, ethyl, or —CH₂OH; or R⁵ and R²⁴ together with        the boron atom form a 5- or 6-membered boron containing ring;    -   R⁶ is —CH₂C(═O)H, —C(═O)NHCH₂C(═O)H, —C(═O)C(═O)N(R¹⁴)₂,        —B(OR²³)(OR²⁴), or

-   -   R^(x) is H, optionally substituted C₁-C₆alkyl, optionally        substituted C₁-C₆heteroalkyl, or optionally substituted        C₃-C₈cycloalkyl; or R^(x) and R² together with the nitrogen atom        form an optionally substituted nitrogen containing ring;    -   R^(y) is H or methyl; or R^(y) and R⁵ together with the nitrogen        atom form an optionally substituted nitrogen containing ring;    -   R⁷ is optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted heterocycloalkyl, optionally        substituted alkenyl, or a linear or branched alkyl chain of        about 1-22 carbon atoms, optionally comprising within the alkyl        chain or at an alkyl chain terminus an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted heterocycloalkyl, or an optionally substituted

wherein Z is a bond, O, S, NH, CH₂, NHCH₂, or C≡C;

-   -   R⁸ is bond, optionally substituted aryl, optionally substituted        heteroaryl, or optionally substituted heterocycloalkyl;    -   R¹⁴ is each independently H, or C₁-C₄alkyl;    -   R¹⁸ is H, or methyl; or R¹⁸ and R¹² together with the atoms to        which they are attached form a heterocycloalkyl ring;    -   each R²¹ is independently H, or C₁-C₄alkyl;    -   each R²² is independently H, C₁-C₄alkyl, —C(═NH)(NH₂), or        —CH(═NH);    -   R²³ and R²⁴ are each independently H, or C₁-C₄alkyl; or R²³ and        R²⁴ together with the boron atom form an optionally substituted        5- or 6-membered boron containing ring; and    -   m is 0-4;    -   or a pharmaceutically acceptable salt, solvate, or prodrug        thereof.

In another embodiment is a compound of Formula (III) having thestructure of Formula (III′):

wherein:

-   -   R² and R⁴ are each independently —H, —CH₃, —CH(CH₃)₂, —C(CH₃)₃,        —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CF₃,        —CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,        —CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²², —(CH₂)₄NR²¹R²²,        optionally substituted C₁-C₈alkyl, optionally substituted        C₁-C₈heteroalkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted —CH₂—C₃-C₈cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl,        optionally substituted heteroaryl,

-   -   R¹² and R¹³ are each independently —H, —NR²¹R²², —CH₃,        —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH,        —CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂,        —CH₂CH₂C(O)NH₂, —CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²²,        —(CH₂)₄NR²¹R²², optionally substituted C₁-C₈alkyl, or optionally        substituted C₁-C₈heteroalkyl; or R¹² and R¹³ together with the        carbon atoms to which they are attached form a heterocycloalkyl        ring;    -   R³ is methyl, ethyl, isopropyl, or cyclopropyl;    -   R⁵ is H, methyl, ethyl, or —CH₂OH; or R⁵ and R²⁴ together with        the boron atom form a 5- or 6-membered boron containing ring;    -   R⁶ is —CH₂C(═O)H, —C(═O)NHCH₂C(═O)H, —C(═O)C(═O)N(R¹⁴)₂,        —B(OR²³)(OR²⁴), or

-   -   R^(x) is H, optionally substituted C₁-C₆alkyl, optionally        substituted C₁-C₆heteroalkyl, or optionally substituted        C₃-C₈cycloalkyl; or R^(x) and R² together with the nitrogen atom        form an optionally substituted nitrogen containing ring;    -   R^(y) is H or methyl; or R^(y) and R⁵ together with the nitrogen        atom form an optionally substituted nitrogen containing ring;    -   R⁷ is optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted heterocycloalkyl, optionally        substituted alkenyl, or a linear or branched alkyl chain of        about 1-22 carbon atoms, optionally comprising within the alkyl        chain or at an alkyl chain terminus an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted heterocycloalkyl, or an optionally substituted

wherein Z is a bond, O, S, NH, CH₂, NHCH₂, or C≡C;

-   -   R⁸ is bond, optionally substituted aryl, optionally substituted        heteroaryl, or optionally substituted heterocycloalkyl;    -   R¹⁴ is each independently H, or C₁-C₄alkyl;    -   R¹⁸ is H, or methyl; or R¹⁸ and R¹² together with the atoms to        which they are attached form a heterocycloalkyl ring;    -   each R²¹ is independently H, or C₁-C₄alkyl;    -   each R²² is independently H, C₁-C₄alkyl, —C(═NH)(NH₂), or        —CH(═NH);    -   R²³ and R²⁴ are each independently H, or C₁-C₄alkyl; or R²³ and        R²⁴ together with the boron atom form an optionally substituted        5- or 6-membered boron containing ring; and    -   m is 0-4;        or a pharmaceutically acceptable salt, solvate, or prodrug        thereof.

In some embodiments is a compound of Formula (III) or Formula (III′)wherein R⁸ is a bond. In a further embodiment is a compound of Formula(III) or Formula (III′) wherein R² and R⁴ are each independently —H,—CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH,—CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂,—CH₂CH₂C(O)NH₂, —CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²², or—(CH₂)₄NR²¹R²². In yet a further embodiment is a compound of Formula(III) or Formula (III′) wherein R² and R⁴ are each independently—CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃),—CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NR²¹R²²,(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²², or —(CH₂)₄NR²¹R²².

In another embodiment is a compound of Formula (III) or Formula (III′)wherein R¹² and R¹³ together with the carbon atoms to which they areattached form a heterocycloalkyl ring. In a further embodiment is acompound of Formula (III) or Formula (III′) wherein R¹² and R¹³ togetherwith the carbon atoms to which they are attached form a pyrrolidinering. In yet a further embodiment is a compound of Formula (III) orFormula (III′) wherein R² and R⁴ are each independently —CH(CH₃)₂,—CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂C(O)NH₂,—CH₂CH₂C(O)NH₂, —CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²², or—(CH₂)₄NR²¹R²².

In another embodiment is a compound of Formula (III) or Formula (III′)wherein R¹⁸ and R¹² together with the atoms to which they are attachedform a heterocycloalkyl ring. In a further embodiment is a compound ofFormula (III) or Formula (III′) wherein R¹⁸ and R¹² together with theatoms to which they are attached form a piperidine ring In yet a furtherembodiment is a compound of Formula (III) or Formula (III′) wherein R¹³is H and R² and R⁴ are each independently —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃),—CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,—CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²², or (CH₂)⁴NR²¹R²².

In another embodiment of the aforementioned embodiments of Formula (I),(II), or (III) is a compound wherein R⁷ is a linear or branched alkylchain of about 1-22 carbon atoms. In another embodiment of theaforementioned embodiments of Formula (I), (II), or (III) is a compoundwherein R⁷ is

In another embodiment of the aforementioned embodiments of Formula (I),(II), or (III) is a compound wherein R⁷ is

In another embodiment of the aforementioned embodiments of Formula (I),(II), or (III) is a compound wherein R⁷ is

In another embodiment of the aforementioned embodiments of Formula (I),(II), or (III) is a compound wherein R⁵ is H. In another embodiment ofthe aforementioned embodiments of Formula (I), (II), or (III) is acompound wherein R⁵ is methyl. In another embodiment of theaforementioned embodiments of Formula (I), (II), or (III) is a compoundwherein R⁵ is —CH₂OH. In another embodiment of the aforementionedembodiments of Formula (I), (II), or (III) is a compound wherein R⁶ is—B(OH)₂. In another embodiment of the aforementioned embodiments ofFormula (I), (II), or (III) is a compound wherein R⁶ is —B(OR²³)(OR²⁴)wherein R²³ and R²⁴ together with the boron atom form an optionallysubstituted 5- or 6-membered boron containing ring. In anotherembodiment of the aforementioned embodiments of Formula (I), (II), or(III) is a compound wherein R⁶ is

In another embodiment of the aforementioned embodiments of Formula (I)is a compound wherein R⁵ is methyl, R⁶ is

R⁸ is a bond, and R⁷ is

In another embodiment of the aforementioned embodiments of Formula (I)is a compound wherein R⁵ is methyl, R⁶ is —B(OH)₂, R⁸ is a bond, and R⁷is

In another embodiment of the aforementioned embodiments of Formula (I)is a compound wherein R⁵ is methyl, R⁶ is

R⁸ is a bond, and R⁷ is

In another embodiment of the aforementioned embodiments of Formula (I)is a compound wherein R⁵ is methyl, R⁶ is —B(OH)₂, R⁸ is a bond, and R⁷is

In another embodiment of the aforementioned embodiments of Formula (I)is a compound wherein R⁵ is methyl, R⁶ is

R⁸ is a bond, and R⁷ is

In another embodiment of the aforementioned embodiments of Formula (I)is a compound wherein R⁵ is methyl, R⁶ is —B(OH)₂, R⁸ is a bond, and R⁷is

In another embodiment of the aforementioned embodiments of Formula (I)is a compound wherein R⁵ is methyl, R⁶ is

R⁸ is heteroaryl, and R⁷ is

In another embodiment of the aforementioned embodiments of Formula (I)is a compound wherein R⁵ is methyl, R⁶ is —B(OH)₂, R⁸ is heteroaryl, andR⁷ is

In another embodiment of the aforementioned embodiments of Formula (I′),(II′), or (III′) is a compound wherein R⁷ is a linear or branched alkylchain of about 1-22 carbon atoms. In another embodiment of theaforementioned embodiments of Formula (I′), (II′), or (III′) is acompound wherein R⁷ is

In another embodiment of the aforementioned embodiments of Formula (I′),(II′), or (III′) is a compound wherein R⁷ is

In another embodiment of the aforementioned embodiments of Formula (I′),(II′), or (III′) is a compound wherein R⁷ is

In another embodiment of the aforementioned embodiments of Formula (I′),(II′), or (III′) is a compound wherein R⁵ is H. In another embodiment ofthe aforementioned embodiments of Formula (I′), (II′), or (III′) is acompound wherein R⁵ is methyl. In another embodiment of theaforementioned embodiments of Formula (I′), (II′), or (III′) is acompound wherein R⁵ is —CH₂OH. In another embodiment of theaforementioned embodiments of Formula (I′), (II′), or (III′) is acompound wherein R⁶ is —B(OH)₂. In another embodiment of theaforementioned embodiments of Formula (I′), (II′), or (III′) is acompound wherein R⁶ is —B(OR²³)(OR²⁴) wherein R²³ and R²⁴ together withthe boron atom form an optionally substituted 5- or 6-membered boroncontaining ring. In another embodiment of the aforementioned embodimentsof Formula (I′), (II′), or (III′) is a compound wherein R⁶ is

In another embodiment of the aforementioned embodiments of Formula (I′)is a compound wherein R⁵ is methyl, R⁶ is

R⁸ is a bond, and R⁷ is

In another embodiment of the aforementioned embodiments of Formula (I′)is a compound wherein R⁵ is methyl, R⁶ is —B(OH)₂, R⁸ is a bond, and R⁷is

In another embodiment of the aforementioned embodiments of Formula (I′)is a compound wherein R⁵ is methyl, R⁶ is

R⁸ is a bond, and R⁷ is

In another embodiment of the aforementioned embodiments of Formula (I′)is a compound wherein R⁵ is methyl, R⁶ is —B(OH)₂, R⁸ is a bond, and R⁷is

In another embodiment of the aforementioned embodiments of Formula (I′)is a compound wherein R⁵ is methyl, R⁶ is

R⁸ is a bond, and R⁷ is

In another embodiment of the aforementioned embodiments of Formula (I′)is a compound wherein R⁵ is methyl, R⁶ is —B(OH)₂, R⁸ is a bond, and R⁷is

In another embodiment of the aforementioned embodiments of Formula (I′)is a compound wherein R⁵ is methyl, R⁶ is

R⁸ is heteroaryl, and R⁷ is

In another embodiment of the aforementioned embodiments of Formula (I′)is a compound wherein R⁵ is methyl, R⁶ is —B(OH)₂, R⁸ is heteroaryl, andR⁷ is

In another aspect described herein are compounds of Formula (IV):

wherein:

-   -   R¹ is selected from:

-   -   R², R⁴, R¹⁰, R¹¹, R¹², and R¹³ are each independently —H, —CH₃,        —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH,        —CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂C(O)OR²⁵, —CH₂CH₂C(O)OH,        —CH₂CH₂C(O)OR²⁵, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,        —CH₂CH₂C(O)N(H)C(H)(CH₃)CO₂H, —CH₂CH₂C(O)N(H)C(H)(CO₂H)CH₂CO₂H,        —CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²², —(CH₂)₄NR²¹R²²,        —(CH₂)₄N(R²⁵)₃, —(CH₂)₄N(H)C(O)(2,3-dihydroxybenzene),        optionally substituted C₁-C₈alkyl, optionally substituted        C₁-C₈heteroalkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted —CH₂—C₃-C₈cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl,        optionally substituted heteroaryl,

-   -   R³ is methyl, ethyl, isopropyl, or cyclopropyl;    -   R⁵ is H, methyl, ethyl, or —CH₂OH;    -   R⁶ is —C(═O)OH;    -   R^(x) is H, optionally substituted C₁-C₆alkyl, optionally        substituted C₁-C₆heteroalkyl, or optionally substituted        C₃-C₈cycloalkyl; or R^(x) and R² together with the nitrogen atom        form an optionally substituted nitrogen containing ring;    -   R^(y) is H or methyl; or R^(y) and R⁵ together with the nitrogen        atom form an optionally substituted nitrogen containing ring;    -   R^(z) is —NR¹⁵R¹⁶, —CH₂—NR¹⁵R¹⁶, or —(CH₂)₂—NR¹⁵R¹⁶;    -   R⁷ is optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted heterocycloalkyl, optionally        substituted alkenyl, or a linear or branched alkyl chain of        about 1-22 carbon atoms, optionally comprising within the alkyl        chain or at an alkyl chain terminus an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted heterocycloalkyl, or an optionally substituted

wherein Z is a bond, O, S, NH, CH₂, NHCH₂, or C≡C;

-   -   R⁸ is a bond, —O—, or —N(R¹⁷)—, optionally substituted aryl, or        optionally substituted heteroaryl;    -   R⁹ is —CH₂OH, —CH₂CH(CH₃)₂,

R¹⁵ and R¹⁶ are each independently H, or C₁-C₄alkyl;

-   -   R¹⁷ is H, methyl, ethyl, isopropyl, or cyclopropyl;    -   R¹⁸, R¹⁹, and R²⁰ are each independently H, or methyl;    -   each R²¹ is independently H, or C₁-C₄alkyl;    -   each R²² is independently H, C₁-C₄alkyl, —C(═NH)(NH₂), or        —CH(═NH);    -   each R²⁵ is independently C₁-C₆alkyl;    -   n is 0 or 1;    -   p is 0 or 1; and    -   q is 0 or 1;    -   or a pharmaceutically acceptable salt, solvate, or prodrug        thereof.

In another embodiment is a compound of Formula (IV) having the structureof Formula (IV′):

wherein:

-   -   R¹ is selected from:

-   -   R², R⁴, R¹⁰, R¹¹, R¹², and R¹³ are each independently —H, —CH₃,        —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH,        —CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂C(O)OR²⁵, —CH₂CH₂C(O)OH,        —CH₂CH₂C(O)OR²⁵, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,        —CH₂CH₂C(O)N(H)C(H)(CH₃)CO₂H, —CH₂CH₂C(O)N(H)C(H)(CO₂H)CH₂CO₂H,        —CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²², —(CH₂)₄NR²¹R²²,        —(CH₂)₄N(R²⁵)₃, —(CH₂)₄N(H)C(O)(2,3-dihydroxybenzene),        optionally substituted C₁-C₈alkyl, optionally substituted        C₁-C₈heteroalkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted —CH₂—C₃-C₈cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl,        optionally substituted heteroaryl,

-   -   R³ is methyl, ethyl, isopropyl, or cyclopropyl;    -   R⁵ is H, methyl, ethyl, or —CH₂OH;    -   R⁶ is —C(═O)OH;    -   R^(x) is H, optionally substituted C₁-C₆alkyl, optionally        substituted C₁-C₆heteroalkyl, or optionally substituted        C₃-C₈cycloalkyl; or R^(x) and R² together with the nitrogen atom        form an optionally substituted nitrogen containing ring;    -   R^(y) is H or methyl; or R^(y) and R⁵ together with the nitrogen        atom form an optionally substituted nitrogen containing ring;    -   R^(z) is —NR¹⁵R¹⁶, —CH₂—NR¹⁵R¹⁶, or —(CH₂)₂—NR¹⁵R¹⁶:    -   R⁷ is optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted heterocycloalkyl, optionally        substituted alkenyl, or a linear or branched alkyl chain of        about 1-22 carbon atoms, optionally comprising within the alkyl        chain or at an alkyl chain terminus an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted heterocycloalkyl, or an optionally substituted

wherein Z is a bond, O, S, NH, CH₂, NHCH₂, or C≡C;

-   -   R⁸ is a bond, —O—, or —N(R¹⁷)—, optionally substituted aryl, or        optionally substituted heteroaryl;    -   R⁹ is —CH₂OH, —CH₂CH(CH₃)₂,

-   -   R¹⁵ and R¹⁶ are each independently H, or C₁-C₄alkyl;    -   R¹⁷ is H, methyl, ethyl, isopropyl, or cyclopropyl;    -   R¹⁸, R¹⁹, and R²⁰ are each independently H, or methyl;    -   each R²¹ is independently H, or C₁-C₄alkyl;    -   each R²² is independently H, C₁-C₄alkyl, —C(═NH)(NH₂), or        —CH(═NH);    -   each R²⁵ is independently C₁-C₆alkyl;

n is 0 or 1;

p is 0 or 1; and

q is 0 or 1;

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another aspect is a compound selected from:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a compound selected from:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a compound selected from:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another aspect are hydrates, or metabolites comprising any of theaforementioned compounds.

In another aspect are pharmaceutical compositions comprising any of theaforementioned compounds together with a pharmaceutically acceptableexcipient.

In another aspect described herein is the use of a compound describedherein in the manufacture of a medicament for treatment of a bacterialinfection in a patient.

In another aspect are methods of treating a mammal in need of suchtreatment comprising administering to the mammal an antibacterialeffective amount of any of the aforementioned compounds at a frequencyand for a duration sufficient to provide a beneficial effect to themammal. In a further embodiment, the causative bacteria species of thebacteria infection is an infection involving Pseudomonas aeruginosa,Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonasalcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia,Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli,Citrobacter freundii, Salmonella typhimurium, Salmonella typhi,Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae,Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacteraerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratiamarcescens, Francisella tularensis, Morganella morganii, Proteusmirabilis, Proteus vulgaris, Providencia alcalifaciens, Providenciarettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobactercalcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica,Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia,Bordetella pertussis, Bordetella parapertussis, Bordetellabronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae,Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilusducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamellacatarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacterjejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae,Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes,Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella,Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis,Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroidesovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroideseggerthii, Bacteroides splanchnicus, Clostridium difficile,Mycobacterium tuberculosis, Mycobacterium avium, Mycobacteriumintracellulare, Mycobacterium leprae, Corynebacterium diphtheriae,Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcusagalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcusfaecium, Staphylococcus aureus, Staphylococcus epidermidis,Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcushyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcushominis, or Staphylococcus saccharolyticus. In another embodiment thebacterial infection is an infection involving a gram negative bacteria.In a further embodiment, the bacterial infection is an infectioninvolving a gram positive bacteria. In another embodiment, the mammalhas a bacteria-related infection that is resistant to treatment witharylomycin A2.

In another aspect are methods of treating a mammal in need of suchtreatment comprising administering to the mammal arylomycin A and/orarylomycin B and/or any of the aforementioned compounds, wherein theinfection involves a bacterial species that expresses a signal peptidasewithout a proline residue within 10 amino acids N-terminal to the signalpeptidase catalytic serine. In a further embodiment, the bacterialspecies encodes or expresses an SPase enzyme without a proline residue 5to 7 amino acids N-terminal to the SPase catalytic serine. In anotherembodiment, the bacteria infection is an infection involvingCorynebacterium diphtheriae, Corynebacterium glutamicum, Campylobacterjejuni, Chlamydia trachomatis, Chlamydophila pneumoniae, Francisellatularensis, Helicobacter pylori, Lactococcus lactis subsp. cremoris,Lactococcus lactis subsp. lactis, Propionibacterium acnes, Rhodococcusequi, Staphylococcus carnosus, Staphylococcus cohnii, Staphylococcushaemolyticus, Staphylococcus hominis, Staphylococcus hominis subsp.hominis, Staphylococcus hominis subsp. novobiosepticus, Staphylococcuslugdunensis, Streptococcus agalactiae, Streptococcus dysgalactiae,Streptococcus mitis, Streptococcus oralis, Streptococcus pyogenes,and/or Streptococcus pnemoniae. In another embodiment the bacterialinfection is an infection involving a gram negative bacteria. In anotherembodiment, administering comprises a topical administration.

In another aspect are methods of treating a mammal in need of suchtreatment comprising administering to the mammal any one or anycombination of the aforementioned compounds, wherein the infectioninvolves a bacterial species that expresses a signal peptidase without aproline residue within 10 amino acids N-terminal to the signal peptidasecatalytic serine. In a further embodiment, the bacterial species encodesor expresses an SPase enzyme without a proline residue 5 to 7 aminoacids N-terminal to the SPase catalytic serine. In another embodiment,the bacteria infection is an infection involving Staphylococcus capitis,Staphylococcus caprae and/or Yersinia pestis.

In a further embodiment are methods of treating a mammal in need of suchtreatment comprising administering to the mammal a second therapeuticagent to any of the aforementioned methods of treatment. In anotherembodiment, the second therapeutic agent is a non-arylomycin antibiotic.In another embodiment, the non-arylomycin antibiotic is anaminoglycoside antibiotic, fluoroquinolone antibiotic, penicillinantibiotic, cephalosporin antibiotic, macrolide antibiotic, glycopeptideantibiotic, rifampicin, chloramphenicol, fluoramphenicol, colistin,mupirocin, bacitracin, daptomycin, or linezolid.

In one embodiment, is a compound described herein which displaysantibiotic activity useful in the treatment of bacterial infections,such as by way of example only, various strains of S. aureus, S.pneumoniae, E. faecalis, E. faecium, B. subtilis and E. coli includingspecies that are resistant to many known antibiotics such asmethicillin-resistant S. aureus (MRSA), vancomycin-resistantEnterococcus sp. (VRE), multidrug-resistant E. faecium,macrolide-resistant S. aureus and S. epidermidis, andlinezolide-resistant S. aureus and E. faecium.

Methicillin-Resistant Staphylococcus aureus

Staphylococcus aureus (S. aureus), a spherical bacterium, is the mostcommon cause of staph infections. S. aureus has been known to cause arange of illnesses from minor skin infections, such as pimples,impetigo, boils, cellulitis folliculitis, furuncles, carbuncles, scaldedskin syndrome, abscesses, to life-threatening diseases such aspneumonia, meningitis, osteomyelitis endocarditis, toxic shock syndrome,and septicemia. Further, S. aureus is one of the most common causes ofnosocomial infections, often causing postsurgical wound infections.

Methicillin was introduced in the late 1950s to treat infections causedby penicillin-resistant S. aureus. It has been reported previously thatS. aureus isolates had acquired resistance to methicillin(methicillin-resistant S. aureus, MRSA). The methicillin resistance gene(mecA) encodes a methicillin-resistant penicillin-binding protein thatis not present in susceptible strains. mecA is carried on a mobilegenetic element, the staphylococcal cassette chromosome mec (SCCmec), ofwhich four forms have been described that differ in size and geneticcomposition. The methicillin-resistant penicillin-binding protein allowsfor resistance to β-lactam antibiotics and obviates their clinical useduring MRSA infections.

In one aspect is a method for treating a subject having a resistantbacterium comprising administering to the subject a compound of Formula(I), (I′), (II), (II′), (III), or (III′) or a pharmaceuticallyacceptable salt, ester, solvate, alkylated quaternary ammonium salt,stereoisomer, tautomer or prodrug thereof. In one embodiment, thebacterium is a Gram-positive bacteria. In another embodiment, theGram-positive bacterium is S. aureus. In further embodiment, the S.aureus is resistant or refractory to a beta-lactam antibiotic. In yet afurther embodiment, the beta-lactam antibiotic belongs to the class ofpenicillins. In a further embodiment, the beta-lactam antibiotic ismethicillin. In yet another embodiment, the subject has amethicillin-resistant S. aureus bacteria. In one embodiment thebeta-lactam antibiotic is flucloxacillin. In another embodiment is amethod for treating a subject having a dicloxacillin-resistant bacteriacomprising administering to the subject a compound of Formula (I), (I′),(II), (II′), (III), or (III′) or a pharmaceutically acceptable salt,ester, solvate, alkylated quaternary ammonium salt, stereoisomer,tautomer or prodrug thereof wherein the subject is refractory todicloxacillin. Also disclosed herein is a method for treating a subjecthaving a methicillin-resistant bacteria comprising administering acompound of Formula (I), (I′), (II), (II′), (III), or (III′) or apharmaceutically acceptable salt, ester, solvate, alkylated quaternaryammonium salt, stereoisomer, tautomer or prodrug thereof wherein thesubject has been determined to have a methicillin-resistant bacteria. Inone embodiment the subject is screened for methicillin-resistantbacteria. In another embodiment, the subject screening is performedthrough a nasal culture. In a further embodiment themethicillin-resistant bacteria is detected by swabbing the nostril(s) ofthe subject and isolating the bacteria. In another embodiment, Real-timePCR and/or Quantitative PCR is employed to determine whether the subjecthas a methicillin-resistant bacteria.

In one embodiment is a method for treating a subject having afirst-generation cephalosporin-resistant bacteria comprisingadministering a compound of Formula (I) or (I), (I′), (Ia), (Ib), (Ibb),(Ic), (Id), (Ie), (II), or (II′) or a pharmaceutically acceptable salt,ester, solvate, alkylated quaternary ammonium salt, stereoisomer,tautomer or prodrug thereof wherein the subject is refractory to afirst-generation cephalosporin. In one embodiment, the bacteria isresistant to a first-generation cephalosporin. In a further embodiment,the bacteria is resistant to cefacetrile. In another embodiment, thebacteria is resistant to cefadroxil. In yet another embodiment, thebacteria is resistant to cefalexin. In one embodiment, the bacteria isresistant to cefaloglycin. In another embodiment, the bacteria isresistant to cefalonium. In another embodiment, the bacteria isresistant to cefaloridine. In yet another embodiment, the bacteria isresistant to cefalotin. In a further embodiment, the bacteria isresistant to cefapirin. In yet a further embodiment, the bacteria isresistant to cefatrizine. In one embodiment, the bacteria is resistantto cefazaflur. In another embodiment, the bacteria is resistant tocefazedone. In yet another embodiment, the bacteria is resistant tocefazolin. In a further embodiment, the bacteria is resistant tocefradine. In yet a further embodiment, the bacteria is resistant tocefroxadine. In one embodiment, the bacteria is resistant to ceftezole.

In one embodiment is a method for treating a subject having asecond-generation cephalosporin-resistant bacteria comprisingadministering a compound of Formula (I) or (I), (I′), (Ia), (Ib), (Ibb),(Ic), (Id), (Ie), (II), or (II′) or a pharmaceutically acceptable salt,ester, solvate, alkylated quaternary ammonium salt, stereoisomer,tautomer or prodrug thereof wherein the subject is refractory to asecond-generation cephalosporin. In another embodiment, the bacteria isresistant to a second-generation cephalosporin. In a further embodiment,the bacteria is resistant to cefaclor. In another embodiment, thebacteria is resistant to cefonicid. In yet another embodiment, thebacteria is resistant to cefprozil. In one embodiment, the bacteria isresistant to cefuroxime. In another embodiment, the bacteria isresistant to cefuzonam. In another embodiment, the bacteria is resistantto cefmetazole. In yet another embodiment, the bacteria is resistant tocefotetan. In a further embodiment, the bacteria is resistant tocefoxitin.

In one embodiment is a method for treating a subject having athird-generation cephalosporin-resistant bacteria comprisingadministering a compound of Formula (I), (I′), (II), (II′), (III), or(III′) or a pharmaceutically acceptable salt, ester, solvate, alkylatedquaternary ammonium salt, stereoisomer, tautomer or prodrug thereofwherein the subject is refractory to a third-generation cephalosporin.In another embodiment, the bacteria is resistant to a third-generationcephalosporin. In a further embodiment, the bacteria is resistant tocefcapene. In another embodiment, the bacteria is resistant tocefdaloxime. In yet another embodiment, the bacteria is resistant tocefdinir. In one embodiment, the bacteria is resistant to cefditoren. Inanother embodiment, the bacteria is resistant to cefixime. In anotherembodiment, the bacteria is resistant to cefmenoxime. In yet anotherembodiment, the bacteria is resistant to cefodizime. In a furtherembodiment, the bacteria is resistant to cefotaxime. In yet a furtherembodiment, the bacteria is resistant to cefpimizole. In one embodiment,the bacteria is resistant to cefpodoxime. In another embodiment, thebacteria is resistant to cefteram. In yet another embodiment, thebacteria is resistant to ceftibuten. In a further embodiment, thebacteria is resistant to ceftiofur. In yet a further embodiment, thebacteria is resistant to ceftiolene. In one embodiment, the bacteria isresistant to ceftizoxime. In another embodiment, the bacteria isresistant to ceftriaxone. In yet another embodiment, the bacteria isresistant to cefoperazone. In yet a further embodiment, the bacteria isresistant to ceftazidime.

In one embodiment is a method for treating a subject having afourth-generation cephalosporin-resistant bacteria comprisingadministering a compound of Formula (I), (I′), (II), (II′), (III), or(III′) or a pharmaceutically acceptable salt, ester, solvate, alkylatedquaternary ammonium salt, stereoisomer, tautomer or prodrug thereofwherein the subject is refractory to a fourth-generation cephalosporin.In another embodiment, the bacteria is resistant to a fourth-generationcephalosporin. In a further embodiment, the bacteria is resistant tocefclidine. In another embodiment, the bacteria is resistant tocefepime. In yet another embodiment, the bacteria is resistant tocefluprenam. In one embodiment, the bacteria is resistant to cefoselis.In another embodiment, the bacteria is resistant to cefozopran. Inanother embodiment, the bacteria is resistant to cefpirome. In yetanother embodiment, the bacteria is refractory to cefquinome.

In one embodiment is a method for treating a subject having acarbapenem-resistant bacteria comprising administering a compound ofFormula (I), (I′), (II), (II′), (III), or (III′) or a pharmaceuticallyacceptable salt, ester, solvate, alkylated quaternary ammonium salt,stereoisomer, tautomer or prodrug thereof wherein the subject isrefractory to a carbapenem. In another embodiment, the bacteria isresistant to a carbapenem. In a further embodiment, the bacteria isresistant to imipenem. In another embodiment, the bacteria is resistantto meropenem. In yet another embodiment, the bacteria is resistant toertapenem. In one embodiment, the bacteria is resistant to faropenem. Inanother embodiment, the bacteria is resistant to doripenem. In anotherembodiment, the bacteria is resistant to panipenem. In yet anotherembodiment, the bacteria is resistant to biapenem,

Vancomycin-Intermediate and Vancomycin-Resistant Staphylococcus aureus

Vancomycin-intermediate Staphylococcus aureus and vancomycin-resistantstaphylococcus aureus are specific types of antimicrobial-resistantStaph bacteria that are refractory to vancomycin treatment. S. aureusisolates for which vancomycin MICs are 4-8 μg/mL are classified asvancomycin-intermediate and isolates for which vancomycin MICs are ≧16μg/mL are classified as vancomycin-resistant (Clinical and LaboratoryStandards Institute/NCCLS. Performance Standards for AntimicrobialSusceptibility Testing. Sixteenth informational supplement. M100-S16.Wayne, Pa.: CLSI, 2006).

As used herein, the term “minimum inhibitory concentration” (MIC) refersto the lowest concentration of an antibiotic that is needed to inhibitgrowth of a bacterial isolate in vitro. A common method for determiningthe MIC of an antibiotic is to prepare several tubes containing serialdilutions of the antibiotic, that are then inoculated with the bacterialisolate of interest. The MIC of an antibiotic is determined from thetube with the lowest concentration that shows no turbidity (no growth).

In one aspect is a method of treating a subject having a bacterialinfection comprising administering to the subject a compound of Formula(I), (I′), (II), (II′), (III), or (III′) or a pharmaceuticallyacceptable salt, ester, solvate, alkylated quaternary ammonium salt,stereoisomer, tautomer or prodrug thereof wherein the bacterialinfection comprises a vancomycin-intermediate Staphylococcus aureusbacterium. In one embodiment, the vancomycin-intermediate Staphylococcusaureus bacterium has a MIC of between about 4 to about 8 μg/mL. Inanother embodiment, the vancomycin-intermediate Staphylococcus aureusbacterium has a MIC of about 4 μg/mL. In yet another embodiment, thevancomycin-intermediate Staphylococcus aureus bacterium has a MIC ofabout 5 μg/mL. In a further embodiment, the vancomycin-intermediateStaphylococcus aureus bacterium has a MIC of about 6 μg/mL. In yet afurther embodiment, the vancomycin-intermediate Staphylococcus aureusbacterium has a MIC of about 7 μg/mL. In one embodiment, thevancomycin-intermediate Staphylococcus aureus bacterium has a MIC ofabout 8 μg/mL.

In another aspect is a method of treating a subject having a bacterialinfection comprising administering to the subject a compound of Formula(I), (I′), (II), (II′), (III), or (III′) or a pharmaceuticallyacceptable salt, ester, solvate, alkylated quaternary ammonium salt,stereoisomer, tautomer or prodrug thereof wherein the bacterialinfection comprises a vancomycin-resistant Staphylococcus aureusbacterium. In one embodiment, the vancomycin-resistant Staphylococcusaureus bacterium has a MIC of between about 16 μg/mL. In anotherembodiment, the vancomycin-resistant Staphylococcus aureus bacterium hasa MIC of about ≧16 μg/mL. In yet another embodiment, thevancomycin-resistant Staphylococcus aureus bacterium has a MIC of about20 μg/mL. In a further embodiment, the vancomycin-resistantStaphylococcus aureus bacterium has a MIC of about 25 μg/mL.

In one embodiment, conditions treated by the compounds described hereininclude, but are not limited to, endocarditis, osteomyelitis,neningitis, skin and skin structure infections, genitourinary tractinfections, abscesses, and necrotizing infections. In anotherembodiment, the compounds disclosed herein are used to treat conditions,such as, but not limited to, diabetic foot infections, decubitus ulcers,burn infections, animal or human bite wound infections,synergistic-necrotizing gangrene, necrotizing fascilitis,intra-abdominal infection associated with breeching of the intestinalbarrier, pelvic infection associated with breeching of the intestinalbarrier, aspiration pneumonia, and post-operative wound infections. Inanother embodiment, the conditions listed herein are caused by, contain,or result in the presence of VISA and/or VRSA.

Vancomycin-Resistant Enterococci

Enterococci are bacteria that are normally present in the humanintestines and in the female genital tract and are often found in theenvironment. These bacteria sometimes cause infections. In some cases,enterococci have become resistant to vancomycin (also known asvancomycin-resistant enterococci or VRE.) Common forms of resistance tovancomycin occur in enterococcal strains that involve the acquisition ofa set of genes endoding proteins that direct peptidoglycan precursors toincorporate D-Ala-D-Lac instead of D-Ala-D-Ala. The six different typesof vancomycin resistance shown by enterococcus are: Van-A, Van-B, Van-C,Van-D, Van-E and Van-F. In some cases, Van-A VRE is resistant to bothvancomycin and teicoplanin, while in other cases, Van-B VRE is resistantto vancomycin but sensitive to teicoplanin; in further cases Van-C ispartly resistant to vancomycin, and sensitive to teicoplanin.

In one aspect, is a method of treating a subject having avancomycin-resistant enterococci comprising administering to the subjecta compound of Formula (I), (I′), (II), (II′), (III), or (III′) or apharmaceutically acceptable salt, ester, solvate, alkylated quaternaryammonium salt, stereoisomer, tautomer or prodrug thereof wherein theenterococci has developed resistance to vancomycin. In one embodiment,the subject has been previously treated with vancomycin for a sustainedperiod of time. In another embodiment, the subject has beenhospitalized. In yet another embodiment, the subject has a weakenedimmune system such as patients in Intensive Care Units or in cancer ortransplant wards. In a further embodiment, the subject has undergonesurgical procedures such as, for example, abdominal or chest surgery. Inyet a further embodiment, the subject has been colonized with VRE. Inone embodiment, the subject has a medical device such that an infectionhas developed. In another embodiment, the medical device is a urinarycatheter or central intravenous (IV) catheter.

In another embodiment, is a method of treating a subject having avancomycin-resistant enterococci comprising administering to the subjecta compound of Formula (I), (I′), (II), (II′), (III), or (III′) or apharmaceutically acceptable salt, ester, solvate, alkylated quaternaryammonium salt, stereoisomer, tautomer or prodrug thereof wherein theenterococcus has Van-A resistance.

In another embodiment, is a method of treating a subject having avancomycin-resistant enterococci comprising administering to the subjecta compound of Formula (I), (I′), (II), (II′), (III), or (III′) or apharmaceutically acceptable salt, ester, solvate, alkylated quaternaryammonium salt, stereoisomer, tautomer or prodrug thereof wherein theenterococcus has Van-B resistance.

In another embodiment, is a method of treating a subject having avancomycin-resistant enterococci comprising administering to the subjecta compound of Formula (I), (I′), (II), (II′), (III), or (III′) or apharmaceutically acceptable salt, ester, solvate, alkylated quaternaryammonium salt, stereoisomer, tautomer or prodrug thereof wherein theenterococcus has Van-C resistance.

Administration and Pharmaceutical Composition

Pharmaceutical compositions described herein comprise a therapeuticallyeffective amount of a compound described herein (i.e., a compound of anyof Formula (I), (I′), (II), (II′), (III), or (III′)) formulated togetherwith one or more pharmaceutically acceptable carriers. As used herein,the term “pharmaceutically acceptable carrier” means a non-toxic, inertsolid, semi-solid or liquid filler, diluent, encapsulating material orformulation auxiliary of any type. Some examples of materials which canserve as pharmaceutically acceptable carriers are sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of theformulator. The pharmaceutical compositions described herein can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, or as an oral or nasal spray, ora liquid aerosol or dry powder formulation for inhalation.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsoptionally contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions are optionally formulated according to the knownart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation is optionally a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that are optionally employed arewater, Ringer's solution, U.S.P. and isotonic sodium chloride solution.In addition, sterile, fixed oils are conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil canbe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid are used in the preparation ofinjectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This is optionally accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is optionally accomplished by dissolving or suspending the drug inan oil vehicle. Injectable depot forms are made by formingmicroencapsule matrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are optionally prepared by entrapping the drug in liposomesor microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compound describedherein (i.e., a compound of any of Formula (I), (I′), (II), (II′),(III), or (III′)) with suitable non-irritating excipients or carrierssuch as cocoa butter, polyethylene glycol or a suppository wax which aresolid at ambient temperature but liquid at body temperature andtherefore melt in the rectum or vaginal cavity and release the activecompound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,acetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form optionally comprises buffering agents.

Solid compositions of a similar type are optionally employed as fillersin soft and hard-filled gelatin capsules using such excipients aslactose or milk sugar as well as high molecular weight polyethyleneglycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings known in the pharmaceutical formulating art.They optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

Solid compositions of a similar type are optionally employed as fillersin soft and hard-filled gelatin capsules using such excipients aslactose or milk sugar as well as high molecular weight polyethyleneglycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings known in the pharmaceutical formulating art. In such soliddosage forms the active compound is optionally admixed with at least oneinert diluent such as sucrose, lactose or starch. Such dosage formsoptionally comprise, as is normal practice, additional substances otherthan inert diluents, e.g., tableting lubricants and other tableting aidssuch a magnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms optionally comprisebuffering agents. They optionally contain opacifying agents and can alsobe of a composition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compounddescribed herein include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as are optionallyrequired. Ophthalmic formulations, ear drops, and the like are alsocontemplated.

The ointments, pastes, creams and gels may contain, in addition to anactive compound described herein, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Compositions described herein are optionally formulated for delivery asa liquid aerosol or inhalable dry powder. Liquid aerosol formulationsare optionally nebulized predominantly into particle sizes that can bedelivered to the terminal and respiratory bronchioles where bacteriareside in patients with bronchial infections, such as chronic bronchitisand pneumonia. Pathogenic bacteria are commonly present throughoutairways down to bronchi, bronchioli and lung parenchema, particularly interminal and respiratory bronchioles. During exacerbation of infection,bacteria can also be present in alveoli. Liquid aerosol and inhalabledry powder formulations are preferably delivered throughout theendobronchial tree to the terminal bronchioles and eventually to theparenchymal tissue.

Aerosolized formulations described herein are optionally delivered usingan aerosol forming device, such as a jet, vibrating porous plate orultrasonic nebulizer, preferably selected to allow the formation of aaerosol particles having with a mass medium average diameterpredominantly between 1 to 5μ. Further, the formulation preferably hasbalanced osmolarity ionic strength and chloride concentration, and thesmallest aerosolizable volume able to deliver effective dose of thecompounds described herein compound described herein (i.e., a compoundof any of Formula (I), (I′), (II), (II′), (III), or (III′)) to the siteof the infection. Additionally, the aerosolized formulation preferablydoes not impair negatively the functionality of the airways and does notcause undesirable side effects.

Aerosolization devices suitable for administration of aerosolformulations described herein include, for example, jet, vibratingporous plate, ultrasonic nebulizers and energized dry powder inhalers,that are able to nebulize the formulation into aerosol particle sizepredominantly in the size range from 1-5 microns. Predominantly in thisapplication means that at least 70% but preferably more than 90% of allgenerated aerosol particles are within 1-5 micron range. A jet nebulizerworks by air pressure to break a liquid solution into aerosol droplets.Vibrating porous plate nebulizers work by using a sonic vacuum producedby a rapidly vibrating porous plate to extrude a solvent droplet througha porous plate. An ultrasonic nebulizer works by a piezoelectric crystalthat shears a liquid into small aerosol droplets. A variety of suitabledevices are available, including, for example, AeroNeb™ and AeroDose™vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, Calif.),Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC®and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc.,Richmond, Va.), and Aerosonic™ (DeVilbiss Medizinische Produkte(Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare,Inc., Vernon Hills, Ill.) ultrasonic nebulizers.

In some embodiments, compounds described herein compound describedherein (i.e., a compound of any of Formula (I), (I′), (II), (II′),(III), or (III′)) are formulated for use as topical powders and spraysthat contain, in addition to the compounds described herein, excipientssuch as lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Spraysoptionally contain customary propellants such aschlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

According to the methods of treatment described herein, bacterialinfections are treated or prevented in a patient such as a human orlower mammal by administering to the patient a therapeutically effectiveamount of a compound described herein, in such amounts and for such timeas is necessary to achieve the desired result. By a “therapeuticallyeffective amount” of a compound described herein is meant a sufficientamount of the compound to treat bacterial infections, at a reasonablebenefit/risk ratio applicable to any medical treatment. It will beunderstood, however, that the total daily usage of the compounds andcompositions described herein will be decided by the attending physicianwithin the scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors known in themedical arts.

The total daily dose of the compounds described herein compounddescribed herein (i.e., a compound of any of Formula (I), (I′), (II),(II′), (III), or (III′)) administered to a human or other mammal insingle or in divided doses can be in amounts, for example, from 0.01 to50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.Single dose compositions may contain such amounts or submultiplesthereof to make up the daily dose. In general, treatment regimensdescribed herein comprise administration to a patient in need of suchtreatment from about 10 mg to about 2000 mg of the compound(s) describedherein per day in single or multiple doses.

EXAMPLES Example 1

General Method 1:

The preparation of fully protected peptide fragments. Fully protectedpeptide fragments four to six amino acids in length terminated by alipophilic carboxylic acid tail are synthesized on solid phase usingchlorotrityl functionalized polystyrene resin (Trt-Cl) and anFmoc/tBu/Trt/t-Boc protecting group strategy and is depicted in SchemeI. Cleavage of the fully protected peptide 1 is accomplished by repeatedtreatment of the resin with 1% TFA in CH₂Cl₂ and aqueous workup of thecombined filtrates. A representative example of General Method 1 isdepicted in Scheme 1A to afford peptide 1A.

General Method 2:

The synthesis of aldehydes. The peptides from General Method 1 are usedin the next steps without further purification as depicted in Scheme II.The peptide 1 is dissolved in a N,N-dimethylformamide, and to thereaction is sequentially added hydroxybenzotriazole (HOBt),aminoacetaldehyde dimethyl acetal (R═H) or 2-aminopropionaldehydedimethyl acetal (R=Me) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDC). The reaction is then sealed and heated to 50° C. for 3 hrs. Thereaction is then cooled to room temperature and diluted with water, 10%citric acid and ethyl acetate. The aqueous phase is extracted with ethylacetate and the combined organic layers are washed with sodiumbicarbonate solution, water and brine then dried over sodium sulfate andconcentrated. The crude material is then treated with a mixture of95:2.5:2.5 trifluoroacetic acid:dichloromethane:water for approximately5 minutes. The volatile solvents are then evaporated, the crude materialis taken up in dichloromethane and evaporated again. The crude materialis purified by HPLC on a Hypersil Gold column (10 mm×250 mm, particlesize—5 micron) to afford the desired compound.

Compound 101: This compound was prepared according to General Method 1and 2 to afford the title compound. MS (ESI) for (C₃₅H₅₄N₈O₁₁): m/z763.1 (M+H).

Example 2

Compound 102: This compound was prepared according to General Method 1and 2 to afford the title compound. MS (ESI) for (C₃₇H₅₉N₇O₁₀): m/z762.1 (M+H).

Example 3

Compound 103: This compound was prepared according to General Method 1and 2 to afford the title compound. MS (ESI) for (C₄₂H₇₄N₈O₁₁): m/z867.3 (M+Na).

Example 4

Compound 104: This compound was prepared according to General Method 1and 2 to afford the title compound. MS (ESI) for (C₃₈H₆₉N₇O₁₀): m/z784.3 (M+H).

Example 5

Compound 105: This compound was prepared according to General Method 1and 2 to afford the title compound. MS (ESI) for (C₄₇H₇₇N₇O₁₁): m/z938.5 (M+Na).

Example 6

Compound 106: This compound was prepared according to General Method 1and 2 to afford the title compound. MS (ESI) for (C₃₇H₆₄N₈O₁₀): m/z767.3 (M+H).

Example 7

Compound 107: This compound was prepared according to General Method 1and 2 to afford the title compound. MS (ESI) for (C₄₀H₇₀N₈O₁₁): m/z839.4 (M+H).

Example 8

Compound 108: This compound was prepared according to General Method 1and 2 to afford the title compound. MS (ESI) for (C₄₃H₇₆N₈O₁₁): m/z881.6 (M+H).

Example 9

Compound 109: This compound was prepared according to General Method 1and 2 to afford the title compound. MS (ESI) for (C₄₄H₇₁N₇O₁₁): m/z874.5 (M+H).

Example 10

Compound 110: The synthesis of Compound 110 is depicted in Scheme III.Peptide 1-110 is prepared according to General Method 1. A solution of1-110 (40 mg, 0.047 mmol) in anhydrous DMF (1 mL) was treated with EDCI(54 mg, 0.28 mmol) and HOBt (31.7 mg, 0.235 mmol) followed by DIEA (18.2mg, 0.141 mmol) and K4 (6.2 mg, 0.047 mmol). The mixture was stirred atroom temperature overnight. After ELSD showed the reaction was complete,the mixture was purified by prep-HPLC to afford 3-110 (17 mg, yield37.4%). To a solution of 3-110 (17 mg, 0.018 mmol) in anhydrousdichloromethane (1 mL) was added Dess-Martin periodinane (22.9 mg, 0.054mmol) in one portion at 0° C. The reaction mixture was allowed to stirat room temperature overnight. After HPLC showed the reaction wascomplete, the mixture was filtered and the filtrate was concentrated invacuo at room temperature to afford 4-110 (16 mg) as a white solid. Asolution of 4-110 (16 mg, 0.016 mmol) in 1 mL of trifluoroacetic acidcontaining 5% water and 5% dichloromethane was stirred at roomtemperature for 15 mins. After ELSD showed the reaction was complete,the solvent was removed. The residue was purified by prep-HPLC (Luna C85 μm 150×21.2 mm) to afford Compound 110 (1.6 mg, yield 13.7%) as amixture of diastereomers. MS (ESI) for (C₄₁H₇₄N₈O₁₁): m/z 855.5 (M+H).

The preparation of K4 is depicted in Scheme IV.

A mixture of nitroethane (3.6 g, 0.5 mol) and Amberlyst A-12 (20 g) in1,2-dichloroethane (30 mL) was cooled to 0° C. K1 (5 g, 50% solution intoluene) was added. The resulting mixture was stirred at roomtemperature overnight. The mixture was filtered and the filtrate wasconcentrated in vacuo to give K2 (4.2 g, 97% yield), as an oil.

A mixture of K2 (0.2 g, 1.1 mmol) and Raney nickel (0.2 g) in ethanol (5mL) was subjected to hydrogen gas at 30 psi hydrogen at room temperaturefor 10 hrs. The mixture was filtered and the filtrate was concentratedin vacuo to afford K3. The residue was used in the next step withoutfurther purification.

To a 30% solution of methylamine in absolute ethanol (20 mL) was addedK3 (160 mg, 1 mmol). The solution was refluxed for 2 hrs. Afterevaporation of the solvent, the residue was recrystallized fromdichloromethane/ethyl acetate to give K4 (100 mg, 70% yield), as ayellow solid.

Example 11

Compound 111: The synthesis of Compound 111 is depicted in Scheme V.Peptide 1-111 is prepared according to General Method 1. A solution of1-111 (100 mg, 0.1 mmol) in anhydrous DMF (1 mL) was treated with EDCI(115.2 mg, 0.6 mmol) and HOBt (67.5 mg, 0.5 mmol) followed by DIEA (38.7mg, 0.3 mmol) and K4 (13.2 mg, 0.1 mmol). The mixture was stirred atroom temperature overnight. After ELSD showed the reaction wascompleted, the mixture was purified by prep-HPLC (Luna C8, 5 μm,150×21.2 mm) to give 45 mg (40.5%) of 3-111 as a mixture ofdiastereomers. To a solution of 3-111 in 1 mL of anhydrousdichloromethane was added Dess-Martin periodinane (3 eq) in one portionat 0° C. The reaction mixture was allowed to stir at room temperatureovernight. After ELSD showed the reaction was complete, the mixture wasfiltered and the filtrate was concentrated in vacuo at room temperatureto afford 45 mg (100%) of 4-111 as a mixture of diastereomers. Asolution of 4-111 in 1 mL of trifluoroacetic acid containing 5% waterand 5% dichloromethane was stirred at room temperature for 15 minutes.After ELSD showed the reaction was complete, the solvent was removedunder reduced pressure. The residue was purified by prep-HPLC (Luna C8,5 μm, 150×21.2 mm) to afford 2.6 mg (6.8%) of Compound 111 as a mixtureof diastereomers. MS (ESI) for (C₄₆H₇₄N₈O₁₂): m/z 931.5 (M+H).

Example 12

The synthesis of Compound 112 is depicted in Scheme VI. Peptide 1-112 isprepared according to General Method 1. A solution of 1-112 (100 mg,0.096 mmol) in anhydrous DMF (1 mL) was treated with EDCI (96 mg, 0.5mmol) and HOBt (67.5 mg, 0.5 mmol) followed by DIEA (64.5 mg, 0.5 mmol)and K4 (13.2 mg, 0.1 mmol). The mixture was stirred at room temperatureovernight. After ELSD showed the reaction was complete, the mixture waspurified by prep-HPLC (Luna C8, 5 μm, 150×21.2 mm) to give 32 mg (29%)of 3-112 as a mixture of diastereomers. To a solution of 3-112 in 1 mLof anhydrous dichloromethane was added Dess-Martin periodinane (3 equv.)in one portion at 0° C. The reaction mixture was allowed to stir at roomtemperature overnight. After ELSD showed the reaction was complete, themixture was filtered and the filtrate was concentrated in vacuo at roomtemperature to give 31 mg (100%) of 4-112 as a mixture of diastereomers.A solution of 4-112 in 1 mL of trifluoroacetic acid containing 5% waterand 5% dichloromethane was stirred at room temperature for 15 minutes.After ELSD showed the reaction was complete, the solvent was removedunder reduced pressure. The residue was purified by prep-HPLC (Luna C8,5 μm, 150×21.2 mm) to give 5.1 mg (19%) of Compound 112 as a mixture ofdiastereomers. MS (ESI) for (C₅₀H₈₂N₈O₁₂): m/z 987.5 (M+H).

Example 13

Compound 113: The synthesis of Compound 113 is depicted in Scheme VII.Peptide 1A (EXAMPLE 1) was prepared according to General Method 1. Asolution of 1A (100 mg, 0.096 mmol) in anhydrous DMF (1 mL) was treatedwith EDCI (96 mg, 0.5 mmol) and HOBt (67.5 mg, 0.5 mmol) followed byDIEA (64.5 mg, 0.5 mmol) and K4 (13.2 mg, 0.1 mmol). The mixture wasstirred at room temperature overnight. After ELSD showed the reactionwas com the mixture was purified by prep-HPLC (Luna C8, 5 μm, 150×21.2mm) to give 3-113 (40 mg, 38.1% yield). To a solution of 3-113 in 1 mLof anhydrous dichloromethane was added Dess Martin periodinane (3 eq) inone portion at 0° C. The reaction mixture was allowed to stir at roomtemperature overnight. After ELSD showed the reaction was complete, themixture was filtered and the filtrate was concentrated in vacuo at roomtemperature to give 4-113 (40 mg, yield 100%). A solution of 4-113 (40mg, 0.034 mmol) in 1 mL of trifluoroacetic acid containing 5% water and5% dichloromethane was stirred at room temperature for 15 minutes. AfterELSD showed the reaction was complete, the solvent was removed underreduced pressure. The residue was purified by prep-HPLC (Luna C8, 5 μm,150×21.2 mm) to give 6 mg (20%) of Compound 113, as a mixture ofdiastereomers. MS (ESI) for (C₃₈H₅₉N₉O₁₂): 834.4 m/z (M+H).

Example 14

Compound 114: The synthesis of Compound 114 is depicted in Scheme VIII.Peptide 1-114 was prepared according to General Method 1. A solution of1-114 (100 mg, 0.12 mmol) in anhydrous DMF (1 mL) was treated with EDCI(115.2 mg, 0.6 mmol) and HOBt (81 mg, 0.6 mmol) followed by DIEA (77.4mg, 0.6 mmol) and K4 (15.8 mg, 0.12 mmol). The mixture was stirred atroom temperature overnight. After ELSD showed the reaction was complete,the mixture was purified by prep-HPLC (Luna C8, 5 μm, 150×21.2 mm) togive 43 mg (47%) of 3-114 as a mixture of diastereomers. To a solutionof 3-114 in 1 mL of anhydrous dichloromethane was added Dess Martinperiodinane (3 eq.) in one portion at 0° C. The reaction mixture wasallowed to stir at room temperature overnight. After ELSD showed thereaction was complete, the mixture was filtered and the filtrate wasconcentrated in vacuo at room temperature to yield 62 mg (100%) of 4-114as a mixture of diastereomers. A solution of 4-114 in 1 mL oftrifluoroacetic acid containing 5% anisole and 5% thioanisole wasstirred at room temperature for 15 minutes. After ELSD showed thereaction was complete, the solvent was removed. The residue was purifiedby prep-HPLC (Luna C8, 5 μm, 150×21.2 mm) to afford Compound 114 as amixture of diastereomers. MS (ESI) for (C₄₀H₆₄N₈O₁₁): 833.4 m/z (M+H).

Example 15

General Method 3:

Addition of a (bis(trimethylsilyl)amino)methylboronic acid ester to apeptidyl carboxylic acid (Scheme IX). A mixture of a peptidyl carboxylicacid (consisting of 4-7 residues) (1 eq), HATU (1.5-2.0 eq),[bis(trimethylsilyl)amino]methylboronic acid pinacol ester (B1) (2.5 eq)is cooled to 0° C., whereupon dichloromethane (0.1 M) and DMF (0.1 M)are added. Sufficient DMF is added where most of the starting materialis dissolved. Then diisopropylethylamine (DIEA, 3 eq) is added, followedby the addition of water (6 eq). The mixture is allowed to warm to roomtemperature. After 2 to 8 hr, the mixture is partitioned betweendichloromethane and water. The aqueous layer is extracted twice withdichloromethane. The combined organic layers are washed with dilute(0.05 M) HCl, then dilute (0.2 M) NaHCO₃. The organic layers are driedover Na₂SO₄, with a small amount of methanol added if necessary, thenfiltered, and concentrated. The resultant oil was precipitated witheither a cold ether wash or 1:1 ether:hexanes wash to afford thecorresponding amidoboronic acid (5-115), which was carried on withoutfurther purification.

General Method 4:

Acid-catalyzed deprotection of O-t-butyl and/or trityl residues usingthioanisole and anisole as a trap (Scheme IX). To a mixture of theamidoboronic acid (1 eq), anisole (2 eq), and thioanisole (2 eq) isadded dichloromethane (0.02 M), then TFA (0.02 M) at 0° C. in a 1:1ratio. The reaction is allowed to warm to room temperature. The reactionis monitored by LC-MS until starting material has been consumed. Thesolvents were evaporated, and the product precipitated with either coldether or cold ether:hexanes (1:1). The crude product was purified byprep HPLC (Hypersil column, 10×250 mm, 5 micron) to afford the desiredboronic acid product.

Compound 115: Compound 1-115 was prepared according to General Method 1.Compound 1-115 was subjected to General Method 3 and General Method 4 toafford Compound 115. MS (ESI) for (C₃₇H₅₃BN₆O₁₂): m/z 835.2 (M+Na).

Example 16

Compound 116: Compound 1-116 was prepared according to General Method 1.Compound 1-116 was subjected to General Method 3 and General Method 4 toafford Compound 116. MS (ESI) for (C₄₀H₅₇BN₈O₁₂): m/z 875.3 (M+Na).

Example 17

Compound 117: Compound 117 was prepared according to General Methods 1,3, and 4.

Example 18

Compound 118: Compound 118 was prepared according to General Methods 1,3, and 4.

Example 19

Compound 119: Compound 119 was prepared according to General Methods 1,3, and 4.

Example 20

Compound 120: Compound 120 was prepared according to General Methods 1,3, and 4.

Example 21

Compound 121: Compound 121 was prepared according to General Methods 1,3, and 4.

Example 22

Compound 122: Compound 122 was prepared as depicted in Scheme X.Compound 1-122 was prepared according to General Method 1. Compound1-122 (100 mg, 0.117 mmol), HATU (89 mg, 0.234 mmol), then B2 (57.3 mg,0.234 mmol) was placed in an ice bath. To this mixture, 2.4 Ml of DCMand 0.8 Ml of DMF was added. To the mixture was added DIEA (45.4 mg,0.351 mmol). After 15-30 minutes, the reaction was allowed to warm roomtemperature and stirred at room temperature for 30 minutes. After ELSDshowed the reaction was complete, the mixture was extracted with DCM (10Ml) and water (5 Ml). The resulting mixture was extracted with DCM (5Ml×2). The combined organic layers were washed sequentially with diluteHCl (<0.1 M), NaHCO₃ solution and brine. The solvents were evaporated,and the residue was extracted with EA (30-50 Ml):water (10-15 Ml). Theorganic layers were washed sequentially with water (10 Ml), and brine,dried over Na₂SO₄, and filtered. The filtrate was concentrated. Theresidue was crystallized from acetonitrile to give 5-122 (100 mg, 86%).To a solution of 5-122 (70 mg, 0.067 mmol) in 95% TFA/H₂O (1 Ml) wasstirred at room temperature for 2 hrs. Then TFA was evaporated with astream of N₂. The crude residue was dissolved in MeOH and purified byprep-HPLC (Luna C8 5 μm 150×21.2 mm) to give 12 mg (22%) of Compound122. MS (ESI) for (C₃₇H₇₀BN₇O₁₁): m/z 822.5 (M+Na).

Example 23

Compound 123: Compound 123 was prepared according to Scheme XI. Compound1-122 (EXAMPLE 22) was prepared according to General Method 1. Compound1-123 (100 mg, 0.117 mmol), HATU (89 mg, 0.234 mmol), then B3 (60.7 mg,0.234 mmol) were combined in a flask and cooled in an ice bath. To thismixture was added 2.4 Ml DCM and 0.8 Ml DMF. DIEA (45.4 mg, 0.351 mmol)was added to the mixture, and after 15-30 minutes the reaction wasallowed to warm room temperature and stirred at room temperature for 30minutes. After ELSD showed the reaction was complete, the mixture wastreated with DCM (10 Ml) and water (5 Ml). The aqueous layer wasextracted with DCM (10 Ml). The combined organic layers were rinsed withdilute HCl (<0.1 M), then NaHCO₃ solution, then brine, and the solventwas evaporated under reduced pressure. The residue was extracted with EA(30-50 Ml):water (10-15 Ml), and the EA layer was washed with water (10Ml), then brine, dried over Na₂SO₄, filtered and concentrated. Thereside was crystallized from acetonitrile to afford 5-123 (80 mg, 64%).To a solution of 5-123 (25 mg, 0.024 mmol in 95% TFA/H₂O (1 Ml) wasstirred at room temperature for 20 minutes. Then TFA was evaporated witha stream of N₂ and ELSD showed the reaction was completed. The residuewas crystallized from acetonitrile to give the crude product. Then thecrude reside was purified by prep-HPLC (Luna C8 5 μm 150×21.2 mm) togive Compound 123 (5 mg, yield: 54%). MS (ESI) for (C₄₈H₈₆BN₇O₁₁): m/z948.5 (M+H).

Example 24

Compound 124: Compound 124 was prepared according to Scheme XII.Compound 1A (EXAMPLE 1) was prepared according to General Method 1. In arb flask, Compound 1-124 (100 mg, 0.093 mmol), HATU (70 mg, 0.186 mmol),then B2 (39 mg, 0.186 mmol was placed in an ice bath. To this mixturewas added 2.4 mL of DCM and 0.8 mL of DMF. DIEA (24 mg, 0.186 mmol) wasadded, and after 15-30 minutes the reaction was allowed to warm roomtemperature and stirred at room temperature for 30 minutes. After ELSDshowed the reaction was complete, the mixture was treated with DCM (10mL) and water (5 mL). The mixture was extracted with DCM (5 mL×2). Thecombined organic layers were washed sequentially with dilute HCl (<0.1M), NaHCO₃ solution, and brine. The solvent was evaporated, and theresidue was extracted with EA (30-50 mL) and water (10-15 mL). Theorganic layers were washed with water (10 mL), brine, and dried withNa₂SO₄, filtered, and concentrated. The reside was crystallized fromacetonitrile to give 5-124 (100 mg, yield: 85.5%). A solution of 5-124(100 mg, 0.079 mmol) in 95% TFA/H₂O (1 mL) was stirred at roomtemperature for 2 hrs. Then TFA was evaporated and ELSD showed thereaction was completed. The crude reside was purified by prep-HPLC (LunaC8 5 μm 150×21.2 mm) to give Compound 124 (16 mg, 26%). MS (ESI) for(C₃₄H₅₅BN₈O₁₂): m/z 801.3 (M+Na).

Example 25

Compound 125: Compound 125 was prepared according to Scheme XIII.Compound 1-125 was prepared according to General Method 1. Compound1-125 (100 mg, 0.12 mmol), HATU (91.2 mg, 0.24 mmol), and B2 (50 mg,0.24 mmol) were added to a small rb flask and cooled in an ice bath. Tothis mixture was added 2.4 mL DCM and 0.8 mL DMF. DIEA (31 mg, 0.24mmol) was added, and after 15-30 minutes the reaction was allowed towarm room temperature and stirred at room temperature for 30 minutes.After ELSD showed the reaction was complete, the mixture was extractedwith DCM (10 mL) and water (5 mL). The mixture was extracted with DCM (5mL×2). The combined layers were washed sequentially with dilute HCl(<0.1 M), NaHCO₃ solution, and brine. The solvent was evaporated, andthe residue was extracted with EA (30-50 mL):water (10-15 mL). Theorganic layer was washed with sequentially with water (10 mL) and brine,dried Na₂SO₄, filtered and concentrated. The residue was crystallizedfrom acetonitrile to give 5-125 (100 mg, 80.3%). MS (ESI) for(C₃₆H₆₀BN₇O₁₁): m/z 800.3 (M+Na). A solution of 5-125 (40 mg, 0.039mmol) in 95% TFA/H₂O (1 mL) was stirred at room temperature for 2 hrs.Then TFA was evaporated and ELSD showed the reaction was completed. Thenthe crude reside was purified by prep HPLC to give Compound 125 (2.4 mg,7.9%). MS (ESI) for (C₃₆H₆₀BN₇O₁₁): m/z 800.3 (M+Na).

Example 26

Compound 126: This compound was prepared in a manner similar to Compound122 (EXAMPLE 22) from General Methods 1, 3, and 4 to afford the titlecompound.

Example 27

Compound 127: Compound 126 (EXAMPLE 26) (9 mg) was dissolved in MeOH anddiluted with water and acetic acid to a final mixture of 80% MeOH:19%water:1% acetic acid to a final concentration of 5 mg/mL. The solutionwas heated and sonicated as needed to facilitate dissolution. Thereaction was monitored by LC-MS, which indicated a 1:1 mixture ofstarting material:product. Prep HPLC afforded 1 mg of Compound 127.

Example 28

Compound 128: Compound 1-128 was treated in a manner similar to Compound124 (EXAMPLE 24) to afford the title compound.

Examples 29-130

Fully protected peptide fragments up to six amino acids in lengthterminated by a lipophilic carboxylic acid tail are synthesized on solidphase using chlorotrityl functionalized polystyrene resin (Trt-Cl) andan Fmoc/tBu/Trt/t-Boc protecting group strategy. A representative schemeof a four-amino acid fragment terminated with a lipophilic carboxylicacid is depicted in Scheme XIV. Cleavage of the fully protected peptide3F is accomplished by repeated treatment of the resin with 1% TFA inCH₂Cl₂ and aqueous workup of the combined filtrates.

General Method 5:

Attachment of an Fmoc-protected amino acid onto a 2-chlorotrityl resinis depicted in Scheme XV.

Step 1: A mixture of 2-chlorotrityl resin (500 mg, 0.5 mmol),diisopropylethylamine (DIPEA) (0.26 g, 2 mmol) in dry DCM (10 mL) wasadded a solution of an Fmoc-protected amino acid 3A (1.5 mmol) in dryDCM (10 ml) at 0° C. Then the mixture was shaken for 5 hr at roomtemperature. The mixture was filtered and the cake was washed with DCM(30 ml×3), DMF (30 mL×3) and MeOH (30 mL×3) to afford Compound 3A1.

Step 2: To the above resin was added approximately 20% piperidine/DMF(70 mL) to remove the Fmoc group. The mixture was shaken for 10 mins andthe cycle was repeated three times. The mixture was washed with DCM(2×30 mL) and DMF (3×30 mL) to give Compound 3A2.

General Method 6:

Solid phase peptide coupling of varying lengths and Fmoc cleavage fromthe peptide. The coupling of peptide and/or amide fragments of aminoacids in length followed by Fmoc removal is depicted in Scheme XVI.

Step 1: A mixture of amino acid 3B (1.5 eq), HCTU (1.5 eq), HOBT (1.5eq) and DIPEA (1.5 eq) in dry DMF (6-8 mL/eq) was stirred at 20° C. for30 min. Then the above mixture was added to Compound 3A2 (1 eq) andshaken at 20° C. for 1.5 hrs. After LCMS showed the reaction wascompleted, the mixture was filtered and the residue was washed with DMF(3×10 mL/mmol) and DCM (3×10 mL/mmol) to give Compound 3B1. Ananalytical portion of resin 3B1 was treated and mixed in 1% TFA/DCM tocleave the peptide from the resin, and the desired product was detectedby MS with confirmation that no starting material remains. In caseswhere the peptide coupling is slow or does not go to completion, HCTUcan be replaced with EDCI.Step 2: To 3B1 was added 20% piperidine/DMF (70 mL) to remove the Fmocgroup. The mixture was shaken for 10 min and the cycle was repeatedthree times. The mixture was washed with DCM (2×30 mL) and DMF (3×30 mL)to give Compound 3B2. In cases where there is more than one protectedamine present, a protecting group other than Fmoc, for example, t-Boc orCBz, is utilized so only one reactive amine is present after Fmocdeprotection.

Step 3 and Step 4: The process of Step 1 and Step 2 can be repeated on3B2 as depicted in Scheme I.

General Method 7:

The coupling of an amide to a resin on solid phase is depicted in SchemeIV. In cases where a coupling partner is an amide instead of anFmoc-protected amino acid, the following procedure is used and isillustrated in Scheme XVII.

A mixture of amino acid 3D2 (1.5 eq), HCTU (1.5 eq), HOBT (1.5 eq) andDIPEA (1.5 eq) in dry DMF (6-8 mL/eq) was stirred at 20° C. for 30 min.Then the above mixture was added to Compound 3E2 (1 eq) and shaken at20° C. for 1.5 hrs. After LCMS showed the reaction was completed, themixture was filtered and the residue was washed with DMF (3×10 mL/mmol)and DCM (3×10 mL/mmol) to give Compound 3E1.

General Method 8:

Cleavage from the resin with 1% TFA is depicted in Scheme XVIII.

Cleavage of the Compound 3E1 is accomplished by repeated treatment ofthe resin with 1% TFA in CH₂Cl₂ as shown in the following example. Amixture of Compound 3E1 (3 mmol) was treated with 1% TFA/DCM (3-4mL/mmol) for 5 min and filtered. This operation was repeated threetimes. The filtrate was treated with saturated NaHCO₃ solution until pH˜7-8. The aqueous layer was adjusted to pH ˜3-4 with citric acid. Themixture was extracted with DCM (6-8 mL/mmol) three times, then thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to give Compound 3F. The reported yields are based on thetheoretical loading of the chlorotrityl chloride resin.

Compound 129F: The compound was prepared using General Methods 6-8 asshown in Scheme XIX. A mixture of Trt resin (1 g, 1 mmol), Fmoc-Asn(Trt)-OH (1.2 g, 2 mmol) and DIPEA (258 mg, 2 mmol) in dry DCM (20 mL)was shaken at 25° C. for 4 hrs. The mixture was filtered and the cakewas washed with DCM (2×30 mL), DMF (2×30 mL) and MeOH (2×30 mL, toquench the possible unreacted trityl resin). To the above resin wasadded approximately 20% piperidine/DMF (70 mL) to remove the Fmoc group.The mixture was shaken for 10 mins and repeated three times. The mixturewas then washed with DCM (2×30 mL) and DMF (3×30 mL) to give Compound129A2.

A mixture of Fmoc-L-Ala-OH (0.62 g, 2 mmol), HCTU (0.83 g, 2 mmol), HOBT(0.27 g, 2 mmol) and DIPEA (0.26 g, 2 mmol) in dry DMF (20 mL) wasstirred at 25° C. for 20 mins. Then the above mixture was added toCompound 129A2 (1 mmol) and shaken at 25° C. for 1.5 hrs. After LCMSshowed the reaction was completed, the mixture was filtered and theresidue was washed with DCM (2×30 mL) and DMF (3×30 mL). To the aboveresin was added approximately 150 mL 20% piperidine/DMF to remove theFmoc group. The mixture was shaken for 10 mins and repeated three times.The mixture was then washed with DCM (2×30 mL), DMF (3×30 mL) to giveCompound 129B2.

A mixture of Fmoc-L-Thr(tBu)-OH (2 mmol), HCTU (0.83 g, 2 mmol), HOBT(0.27 g, 2 mmol) and DIPEA (0.26 g, 2 mmol) in dry DMF (20 mL) wasstirred at 25° C. for 20 mins. Then the above mixture was added toCompound 129B2 (1 mmol) and shaken at 25° C. for 1.5 hrs. After LCMSshowed the reaction was completed, the mixture was filtered and theresidue was washed with DCM (2×30 mL) and DMF (3×30 mL). To the aboveresin was added approximately 150 mL 20% piperidine/DMF to remove theFmoc group. The mixture was shaken for 10 mins and repeated three times.The mixture was then washed with DCM (2×30 mL), DMF (3×30 mL) to giveCompound 129C2.

A mixture of Fmoc-L-Lys(Boc)-OH (0.62 g, 2 mmol), HCTU (0.83 g, 2 mmol),HOBT (0.27 g, 2 mmol) and DIPEA (0.26 g, 2 mmol) in dry DMF (20 mL) wasstirred at 25° C. for 20 mins. Then the above mixture was added toCompound 129C2 (1 mmol) and shaken at 25° C. for 1.5 hrs. After LCMSshowed the reaction was completed, the mixture was filtered and theresidue was washed with DCM (2×30 mL) and DMF (3×30 mL). To the aboveresin was added approximately 150 mL 20% piperidine/DMF to remove theFmoc group. The mixture was shaken for 10 mins and repeated three times.The mixture was then was washed with DCM (2×30 mL), DMF (3×30 mL) togive Compound 129D2.

A mixture of 4-(4-butylphenyl)benzoic acid (1.5 eq), HCTU (1.5 eq), HOBT(1.5 eq) and DIPEA (1.5 eq) in dry DMF (6-8 mL/eq) was stirred at 20° C.for 30 min. Then the above mixture was added to Compound 129D2 (1 eq)and shaken at 20° C. for 1.5 hrs. After LCMS showed the reaction wascompleted, the mixture was filtered and the residue was washed with DMF(3×10 mL/mmol), DCM (3×10 mL/mmol), THF (3×10 mL/mmol) and petroleumether (3×10 mL/mmol) to give Compound 129E1.

A mixture of Compound 129E1 (1 mmol) was treated with 1% TFA/DCM (4 mL)for 5 min and filtered. This operation was repeated three times. Thefiltrate was treated with saturated NaHCO₃ solution until pH ˜7-8. Theaqueous layer was adjusted to pH ˜3-4 with citric acid. The mixture wasextracted with DCM (8 mL) three times, and then the combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated togive Compound 129F. MS (ESI) m/z 1067.4 (M+H)⁺.

Using the procedures described in General Methods 6-8 and Scheme XIX,the following carboxylic acids were prepared:

Using the procedures described in General Methods 6-8, the followingcarboxylic acids were prepared:

General Method 9:

The coupling of an aminoboronate ester to a carboxylic acid is depictedin Scheme XIX.

Compound 3F (1 eq), HATU (2.0 eq) and aminoboronate ester 3F1 (1.5 eq)was added to a round-bottom flask and cooled in an ice bath. DCM and DMFwere added in a 3:1 ratio (0.03-0.05 M). In cases where solubility islimiting, additional DMF can be added. After 15-30 minutes, the reactionwas allowed to warm to room temperature and stirred for 30 minutes.After LCMS analysis showed the reaction to be complete, the mixture wasdistributed between DCM and water, and the aqueous layer was extractedtwice with DCM. The combined organic layers were washed sequentiallywith diluted HCl (<0.1 M), NaHCO₃ solution, and brine. The solvent wasremoved under reduced pressure. The solid residue was washed withacetonitrile to afford the desired compound. In cases where there isexcessive DMF remaining, the residue was distributed between EA (300mL/mmol) mL):water (100 mL/mmol). The organic layers were washedsequentially with water and brine, and dried over Na₂SO₄. The mixturewas filtered and concentrated, and the resulting solid washed withacetonitrile.

General Method 10:

The deprotection of acid sensitive protecting groups (N-Boc, O-t-butyl,and/or C(O)NH-trityl) with TFA and triethylsilane. A solution of thefully protected Compound 3G (100 mg, 0.070-0.12 mmol) in TFA:DCM:TES(50:45:5) (1 mL) was stirred at room temperature for 30 min. Whenanalysis by LC-MS showed the reaction was complete, the TFA wasevaporated and ELSD showed the reaction was complete. The crude residuewas then taken up in DMSO and purified by prep-HPLC. In cases where themobile phase was acetonitrile/water with 0.1% TFA, the resultant salt isthe TFA salt. In instances where the mobile phase was acetonitrile/waterwith 0.1% HCl, the resultant salt is the HCl salt.

A representative example of General Methods 9 and 10 is shown in SchemeXX.

Compound 173: A flask containing Compound 173F (100 mg, 0.12 mmol), HATU(91 mg, 0.24 mmol), then 3F2 (47 mg, 0.18 mmol) was placed in an icebath. DCM (2.4 mL) and DMF (0.80 mL) were added. To this mixture wasadded DIEA (46.2 mg, 0.358 mmol). After 15-30 mins the reaction waswarmed to room temperature and stirred for 30 mins. After ELSD showedthe reaction was complete, water (1 ml) was added and the mixture wasfiltrated. The filter cake was washed sequentially with water andpetroleum ether to afford Compound 173-I (70 mg, 56%).

A solution of Compound 173-I (70 mg, 0.069 mmol) in TFA:DCM:TES(50:45:5) (1 mL) was stirred at 23° C. for 2 hrs until ELSD showed thereaction was completed, then TFA was evaporated. Then the crude residuewas taken up in DMSO and purified by prep-HPLC to give Compound 173 (13mg, 23%).

General Method 11:

The deprotection of the pinanediol protecting group to the free boronicacid by transesterification with Ph(BOH)₂ is depicted in Scheme XXI.

A solution of the pinanediol (0.05 mmol) in water (2 mL) was stirred forfive minutes until the compound dissolves and forms clear solution.Added ether (3 mL) and phenyl boronic acid (3 eq) dissolved in water (1mL). The mixture was stirred at 25° C. overnight. After LCMS analysisshowed the reaction was complete, the water layer was evaporated underreduced pressure. The crude residue was washed with Et₂O to afford thefree boronic acid (25.0 mg, yield: 74.6%). If further purification isnecessary, the crude product was dissolved in DMSO and purified bypreparative HPLC. In cases where the mobile phase was acetonitrile/waterwith 0.1% TFA, the resultant salt is the TFA salt. In instances wherethe mobile phase was acetonitrile/water with 0.1% HCl, the resultantsalt is the HCl salt. A representative example is shown in Scheme XXII.

A solution of Compound 173 (9.0 mg, 0.011 mmol) in water (2 mL) wasstirred for five minutes until the compound dissolved and formed clearsolution. Ether (3 mL) and a solution of phenyl boronic acid (4.00 mg,0.033 mmol) dissolved in water (1 mL) were added. The mixture wasstirred at 23° C. for 12 h. After LCMS showed the reaction wascompleted, water was evaporated. The crude residue was then washed withEt₂O to give Compound 177 (7.0 mg, yield: 93%) as an off-white solid.

Using the procedures described in General Methods 9 and 10 for thepreparation of the boronate esters or General Methods 9, 10 and 11 forthe preparation of the boronic acids, the following boronate ester orboronic acid were prepared from the corresponding carboxylic aciddescribed above:

Using the procedures described in General Methods 9 and 10 for thepreparation of the boronate esters or General Methods 9, 10, and 11 forthe preparation of the boronic acids, the following boronate ester orboronic acid of varying length were prepared from the correspondingcarboxylic acid described above:

Examples 131-150

Compound 5G: The synthesis of Compound 5G is depicted in Scheme XXIII. Amixture of 2-chlorotrityl resin (0.320 g, 0.416 mmol), DIEA (0.215 g,1.66 mmol) in dry DCM (15.0 mL) was added to a solution ofFmoc-L-Lys(Boc)-OH (0.389 g, 0.832 mmol) in dry DCM (10.0 mL) at 0° C.The mixture was then shaken for 5 hrs at room temperature. The mixturewas filtered and the cake was washed with DCM (20.0 mL×3), DMF (20.0mL×3) MeOH (20.0 mL×3). To the above resin was added 20% piperidine/DMF(approximately 20.0 mL) to remove the Fmoc group. The mixture was shakenfor 10 mins and the cycle was repeated three times. The mixture was thenwashed with DCM (20.0 mL×3 mL) and DMF (20.0 mL×3) to give Compound 5A2.

To a mixture of Fmoc-L-Ala-OH (0.259 g, 0.832 mmol) in dry DMF (15.0 mL)was added HCTU (0.344 g, 0.832 mmol), HOBt (0.112 g, 0.832 mmol), DIEA(0.215 g, 1.66 mmol) at 0° C. The mixture was then was stirred at 16° C.for 30 mins. The mixture was added to a suspension of Compound 5A2(0.416 mmol) in DMF (10.0 mL). The mixture was stirred at roomtemperature for 1.5 hrs. After ELSD showed the reaction was completed,the mixture was filtered. The cake was washed with DMF (20.0 mL×3), DCM(20.0 mL×3). To the above resin was added approximately 20.0 mL 20%piperidine/DMF to remove the Fmoc group. The mixture was shaken for 10mins and the cycle was repeated three times. The mixture was then washedwith DCM (20.0 mL×3 mL) and DMF (20.0 mL×3) to give Compound 5B2.

Compound 5C2 was made using the same method as for Compound 5B2 exceptFmoc-L-Thr(tBu)-OH was utilized in the coupling reaction in place ofFmoc-L-Ala-OH.

Compound 5D2 was made from Compound 5C2 using the same method as forCompound 5C2 except Fmoc-L-Dab(Boc)-OH was utilized in the couplingreaction in place of Fmoc-L-Thr(tBu)-OH.

A mixture of Compound 5D2 (2.00 mmol) in TFA/DCM (1%, 20.0 mL) wasshaken at 15° C. for 10 mins. The mixture was then filtered and thefiltrate was treated saturated NaHCO₃ solution until pH=7˜8. The mixturewas treated with DCM (20.0 mL). The aqueous layer was added citric aciduntil pH ˜3-4. The mixture was extracted with DCM (20.0 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to give Compound 5E (1.1 g, 61.5%). MS (ESI) m/z 919.3(M+Na)⁺.

Compound 5E (250 mg, 0.279 mmol), HATU (212 mg, 0.558 mmol) and Compound3F2 (108 mg, 0.419 mmol) were placed in the flask in an ice bath, thenDCM (2.40 mL) and DMF (0.800 mL) were added. DIEA (108 mg, 0.837 mmol)was then added to the mixture. The reaction mixture was stirred at −5°C. for 30 mins. The crude residue was taken up in DMSO. A secondexperiment starting from 250 mg of Compound 5E was repeated and combinedwith this experiment. The combined batches were purified by prep-HPLC togive Compound 5F (200 mg, 81.4%) as white solid. MS (ESI) m/z 1102.4(M+H)⁺.

To a solution of Compound 5F (400 mg, 0.363 mmol) in MeCN (3 ml) wasadded Et₂NH (79.6 mg, 1.09 mmol). The mixture was then stirred at 16° C.for 12 hrs until TLC (DCM:MeOH 10:1, R_(f) ⁼0.5) showed the reaction wascomplete. The mixture was concentrated and the residue was purified bycolumn chromatography to give Compound 5G (280 mg, 87.8%). MS (ESI) m/z880.6 (M+Na)⁺.

General Method 12:

Coupling of Compound 5G with a carboxylic acid in solution phasefollowed by deprotection of acid sensitive protecting groups with TFA inthe presence of a reducing agent. A specific example is shown in SchemeXXIV to illustrate this method.

Compound 231: To a mixture of Compound 5G (60 mg, 0.068 mmol),4-(4t-butylphenyl)benzoic acid (17.3 mg, 0.0683 mmol), EDCI (26.2 mg,0.137 mmol), HOBt (18.4 mg, 0.137 mmol) in DMF (2.00 mL) was added DIEA(17.6 mg, 0.137 mmol). The mixture was then stirred at room temperaturefor 12 hrs. When TLC analysis (DCM:MeOH 10:1, R_(f)=0.5) showed thereaction was complete, the mixture was diluted with water, filtered andthe filter cake was washed with water, dried to afford Compound 231H (50mg, yield: 633%) as brown solid.

A solution of Compound 231H (50.0 mg, 0.0448 mmol) in TFA:DCM:TES(50:45:5) (2.00 mL) was stirred at 12° C. for 0.5 h, then TFA wasremoved and ELSD showed the reaction was complete. The crude residue wastaken up in DMSO and purified by prep-HPLC to give Compound 231 (6.3 mg,16.4%) as an off-white solid. MS (ESI) m/z 860.6 (M+H)⁺.

Using the procedures described in General Method 12, the followingcompounds were prepared:

Example 151

General Method 13:

The synthesis of a biaryl or aryl-heteroaryl carboxylic acid from1-bromo-4-butylbenzene and an aryl- or heteroaryl boronic acid. Anillustration of this method is depicted for 4-(4-butylphenyl)benzoicacid.

A solution of 1-bromo-4-butylbenzene (100 g, 0.472 mol),4-(methoxycarbonyl)phenylboronic acid (82.0 g, 0.456 mol), 2 M Na₂CO₃(150 g, 1.42 mol) in toluene/EtOH (900 mL/300 mL) was degassed with N₂three times, then Pd(PPh₃)₄ (27.2 g, 23.6 mmol) was added. The resultingmixture was degassed with N₂ three times and then heated to reflux for 5hrs. After TLC showed the reaction was complete, toluene and EtOH wasremoved under vacuum. The residue was extracted with EA (30 mL×3). Thecombined organic layers were washed with brine, dried with Na₂SO₄. Thesolvent was removed to give the crude product. The crude product waspurified by column chromatography on silica gel eluted with PE, PE:EA(150:1). The solvent was removed to give methyl4-(4-butylphenyl)benzoate (105 g, yield: 86.0%), as a white solid.

A mixture of methyl 4-(4-butylphenyl)benzoate (89.0 g, 0.332 mol), NaOH(26.6 g, 0.664 mol) in THF/H₂O (500 mL/100 mL) was heated to refluxovernight. After TLC showed the reaction was complete, THF was removed.The residue was adjusted pH ˜3-4 with 2 N HCl solution. The resultingmixture was filtered and the cake was washed with water, dried to give4-(4-butylphenyl)benzoic acid (60.0 g, yield: 71.1%), as a white solid.(ESI) m/z 255.0 (M+H)⁺.

General Method 14:

The synthesis of a biaryl or aryl-heteroaryl carboxylic acid from4-butylbenzeneboronic acid or 4-butylbenzeneboronic acid pinacol esterand an aryl- or heteroaryl halide. An illustration of this method isdepicted for Compound 248A. A solution of 4-butylphenylboronic acidpinacol ester (937 mg, 3.60 mmol) in dioxane/H₂O (40 mL, v/v, 1/1) wasadded Compound 14A (400 mg, 1.80 mmol) and K₂CO₃ (497 mg, 3.60 mmol).The mixture was then degassed with N₂ 3 times before adding Pd(dppf)Cl₂(132 mg, 0.180 mmol) and degassing with N₂ 3 times. The mixture washeated to reflux for 7 hrs. The reaction mixture was cooled to roomtemperature and concentrated after TLC showed the reaction was complete.The residue was adjusted pH ˜4-5 with 1 N HCl solution. After that, theresulting mixture was filtered and the filter cake was washed withwater, dried to give Compound 248A (200 mg, yield: 42.6%), as a brownsolid.

Compound 251: To a mixture of Compound 198G (100 mg, 0.112 mmol), HATU(85.1 mg, 0.224 mmol), and Compound 251A (61.4 mg, 0.168 mmol) in DCM(2.4 mL) and DMF (0.5 mL) at 0° C. was added DIEA (43.3 mg, 0.336 mmol).After 15-30 min the reaction was allowed to warm to room temperature andstirred for 30 min. After ELSD showed the reaction was complete, themixture was extracted with DCM (30 mL) and water (15 mL). The resultingmixture was extracted with DCM (30 mL×2). The combined organic layerswere washed with diluted HCl (<0.1 M), then NaHCO₃ solution, brine. Thesolvent was removed and the residue was extracted with EA (30-50mL):water (10-15 mL). The organic layers were washed with water (2 mL),then brine, dried over Na₂SO₄. The mixture was filtered and the filtratewas concentrated. The crude residue was purified by prep-HPLC to giveCompound 251H (50.0 mg, yield: 37.1%). MS (ESI) m/z 1206.7 (M+H)⁺.

A suspension of Compound 251H (50.0 mg, 0.0415 mmol) and 50% Pd(OH)₂(10.0 mg) in MeOH (2 mL) under H₂ was stirred at 25° C. overnight andELSD showed the reaction was completed. The catalyst was filtered andthe solvent was evaporated, the crude residue was purified by prep-HPLCto give Compound 251I (20.0 mg, yield: 43.2%). MS (ESI) m/z 1116.6(M+H)⁺.

A solution of Compound 251I (10.0 mg, 0.0090 mmol) in TFA:DCM:TES(50:45:5) (1 mL) was stirred at room temperature 2 hrs, then TFA wasevaporated and ELSD showed the reaction was completed. The crude residuewas taken up in DMSO and purified by prep-HPLC to give Compound 251 (2.8mg, yield: 33%). MS (ESI) m/z 960.8 (M+H)⁺.

Example 152

Compound 252: Compound 252G was prepared according General Methods 6-8.MS (ESI) m/z 1153.4. Compound 252 was prepared using the methodsdescribed for Compound 111 from Compound 252G and Compound K4. MS (ESI)m/z 852.2 (M+H)⁺.

Example 153

Compound 253: To a mixture of Boc-L-Ala-OH (50.0 g, 0.265 mol), Compound253B (16.1 g, 0.265 mol), and DIEA (102.4 g, 0.794 mol) in DMF (600 mL)was added HOBt (39.3 g, 0.291 mol) and EDCI (66.0 g, 0.344 mol) at 0° C.The mixture was stirred overnight at 26° C. After LCMS showed thereaction was complete, the mixture was extracted with t-BuOMe and H₂O.The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated to give Compound 253A2 (50.0 g, yield: 81.5%).

A solution of LAH (2.16 g, 51.7 mmol) in dry THF (70 mL) agitated withan overhead stirrer was chilled to 15° C. A solution of Compound 253A2(12.0 g, 51.7 mmol) in dry THF (80 mL) was added with cooling so as tokeep the reaction temperature <5° C. The reaction mixture was stirredfor 45 min quenched by slow addition of EA (20 mL) keeping the internaltemperature <5° C. The combined organic layers were washed with sat. aq.NaHCO₃ and brine, dried with Na₂SO₄, filtered and concentrated to giveCompound 253A3 (10.0 g, yield: >90%).

A solution of Compound 253A3 (10.0 g, 57.8 mmol) in dry DCM (100 mL) wasadded Et₃N (7.01 g, 69.4 mmol) and acetone cyanohydrin (9.83 g, 116mmol) at 26° C. The reaction mixture was stirred overnight at 26° C.After TLC showed the reaction was complete, the reaction mixture wasconcentrated diluted with aqueous 1N HCl (30 mL) and extracted with DCM.The combined organic layers were washed with H₂O and brine, dried overNa₂SO₄, filtered and concentrated to give Compound 253A4 (4.00 g, yield:34.6%).

A mixture of Compound 253A4 (3.00 g, 15.0 mmol) in HCl/MeOH (30 mL) washeated to reflux for 1 hour. After ELSD showed the reaction wascomplete, HCl/MeOH was evaporated to give Compound 253A5 (3.00 g, yield:>90%).

A mixture of Compound 253A5 (3.00 g, 17.7 mmol) in NH₃/THF (30 mL) in asealed tube was heated to 100° C. overnight. After ELSD showed thereaction was complete, the mixture was evaporated to give Compound 253A6(1.30 g, yield: 62.2%). MS (ESI) m/z 852.2 (M+H)⁺.

To a solution of Compound 146F (18 mg, 0.02 mmol) in anhydrous DMF (1mL) was added HATU (15 mg, 0.04 mmol), DIEA (8 μL, 0.06 mmol) and 253A(5 mg, 0.03 mmol). The mixture was stirred at room temperatureovernight. After LCMS showed the reaction was complete, crushed ice wasadded to the reaction mixture and after standing for about an hour awhite solid was precipitated. The solid was filtered and dried to affordCompound 253G. The solid was dissolved in anhydrous DCM (2 mL) and DessMartin Periodinane (DMP, 5 eq, 0.1 mmol, 42 mg) was added. The reactionmixture was stirred for 24 h. After LCMS showed the reaction wascomplete, the reaction mixture was diluted with DCM-EtOAC(1:1), washedwith saturated NaHCO₃ solution and brine, dried (Na₂SO₄) andconcentrated. The residue was purified by ISCO column (DCM and 20%MeOH-DCM) to isolate 9 mg of Compound 253H as a white solid. To asolution of Compound 253H in dioxane (1 mL) was added 4N HCl in dioxane(0.3 mL) at 0° C. and the resulting solution was stirred at rt for 2 hwhile warming up the reaction temperature to rt. After LCMS showed thereaction was complete, the material was allowed stand for about 10minutes. A gummy material formed and the supernatant dioxane was removedand dry ether was added and stirred for 5 min. White precipitate wasformed. Ether layer was removed and the solid was dried to affordCompound 253, a white solid as the bis-HCl salt. MS (ESI) m/z 793.3(M+H)⁺.

Example 154

Compound 254: Compound 254A was prepared in a manner similar to Compound253A using Boc-D-Ala-OH as the starting material. Compound 254 wasprepared in a manner similar to that of Compound 253 from Compound 146Fand Compound 254A. MS (ESI) m/z 793.4 (M+H)⁺.

Example 155

Compound 255: Compound 6D (Tetrahedron (1983) vol 39, no. 15, 2571-2575)was dissolved in DMF and treated with K₂CO₃ (1.1 eq) and iodomethane(2.5 eq) and allowed to stir for 4 hrs. The reaction was then quenchedby the addition of water and a small amount of brine and extracted 3×with EtOAc. The combined organic fractions were washed with 1% citricacid and brine then dried over sodium sulfate and concentrated. Thecrude material was purified by ISCO silica gel chromatography (0-50%EtOAc in Hex, compound eluted at 40% EtOAc) to give Compound 6E (75%yield). ¹H NMR (CDCl₃) δ 7.35 (m, 5H), 5.41 (br s, 1H), 5.112 (s, 2H),4.61 (m, 1H), 3.84 (m, 1H), 3.81 (s, 3H).

To a solution of Compound 6E in EtOH was added 1N HCl (2 eq). Thesolution was then put under nitrogen atmosphere and 10% Pd/C (50% byweight of starting material) was added. The solution was then put underan atmosphere of hydrogen and hydrogen was left to bubble through thesolution. After 3 hrs the mixture was filtered through celite andconcentrated to give crude Compound 6F.

Compound 255F was prepared according to General Methods 6-8. MS (ESI)m/z 963.2 (M+H)⁺.

To a slightly cloudy solution of Compound 255F and Compound 6F (4 eq) inanhydrous DMF was added HATU (1.2 eq) and DIEA (5 eq). The reaction wascomplete as judged by LCMS after 10 min and water and DCM were added.The aqueous layer was extracted 3× with DCM then the combined organicfractions were washed with water (2×) then brine. The solution was thendried over sodium sulfate and concentrated. The crude material was thenpassed through a plug of silica to provide the Compound 255G (75% yield)(MS (ESI) for (C₅₇H₇₂N₈O₁₁): m/z 1067.5 (M+Na).

To a cloudy solution of Compound 255G in EtOH was added 1 N HCl (2 eq).The solution was put under nitrogen atmosphere then 10% Pd/C (100% byweight of the starting material) was added. The mixture was put under anatmosphere of hydrogen and stirred overnight. The mixture was thenfiltered over celite and evaporated to afford Compound 255 by LCMS. MS(ESI) for (C₄₂H₆₇N₈O₇): m/z 815.4 (M+Na).

Example 156

Compound 256: Compound 256F was prepared according to General Methods6-8. MS (ESI) m/z 947.3 (M+H)⁺.

To a solution of Compound 256F and Compound 6F (4 eq) in anhydrous DMFwas added HATU (1.2 eq) and DIEA (5 eq). The reaction was complete asjudged by LCMS after 10 min and water, a small amount of brine and EtOAcwere added. The aqueous layer was extracted 3× with EtOAc then thecombined organic fractions were washed with dilute citric acid, waterthen brine. The solution was then dried over sodium sulfate andconcentrated. The crude material was purified by ISCO silica gelchromatography to provide Compound 256G (41% yield). MS (ESI) for(C₅₇H₇₂N₈O₁₁): m/z 799.4 (M+Na).

To a solution of Compound 256G in EtOH was added 1 N HCl (1.9 eq). Thesolution was put under nitrogen atmosphere then 10% Pd/C (100% by weightof the starting material) was added. The mixture was then put under anatmosphere of hydrogen and stirred overnight. The mixture was filteredthrough celite then the dilute filtrate was checked by LCMS and found togive correct mass (MS (ESI) for (C₄₁H₆₀N₈O₇): m/z 799.4 (M+Na)).

Example 157

To a solution of Compound 6D in anhydrous DMF was added K₂CO₃ (1.1 eq)and methyl bromocetate (1.5 eq). The mixture was stirred at roomtemperature until TLC indicated complete consumption of the startingmaterial after 2.5 hrs then dilute citric acid and EtOAc were added. Theaqueous layer was extracted 3× with EtOAc then the combined organiclayers were washed twice with water then brine. The combined organicsolution were dried over sodium sulfate and concentrated to give crudeproduct then purified by ISCO silica gel chromatography (0 to 65% EtOAcin Hexanes—product eluted at 60% EtOAc) to give Compound 7A (73% yield).¹H NMR (CDCl₃) δ 7.35 (m, 5H), 5.31 (br s, 1H), 5.11 (s, 2H), 4.62 (m,1H), 4.55 (s, 2H), 3.99 (m, 1H), 3.79 (s, 3H), 3.67 (m, 1H).

To a solution of Compound 7A in EtOH was added 1N HCl (2 eq). Thesolution was put under nitrogen atmosphere and the 10% Pd/C (100% byweight of starting material) was added. The solution was then put underan atmosphere of hydrogen and hydrogen was left to bubble through thesolution. After 2 hrs the mixture was filtered through celite andconcentrated to give crude Compound 7B.

A solution of Compound 256F (10 eq) in anhydrous DMF was added toCompound 7B then HATU (1.2 eq) and DIEA (10 eq) were added. The reactionwas stirred at room temperature for 4.5 hrs then water and EtOAc wereadded. The aqueous layer was extracted 2× with EtOAc then the combinedorganic layers were washed with water (2×), dilute citric acid, andbrine then dried over sodium sulfate and concentrated. The crudematerial was then purified by filtration through a silica plug to giveCompound 257G (56% yield) (MS (ESI) for (C₅₉H₇₄N₈O₁₃): m/z 1103.2(M+H)).

To a solution of Compound 257G in EtOH was added 1 N HCl (1.9 eq). Thesolution was put under nitrogen atmosphere then 10% Pd/C (100% by weightof the starting material) was added. The mixture was then put under anatmosphere of hydrogen and stirred overnight. The mixture was filteredthrough celite then the dilute filtrate was checked by LCMS and found togive the correct product. MS (ESI) for (C₄₃H₆₂N₈O₉): m/z 857.4 (M+Na).The filtrate was then concentrated down to an 8 mg/mL solution in EtOHand checked again by LCMS which showed an identical mass spectrum to thediluted sample. Compound 257 was stored as an 8 mg/mL solution.

Example 158

To a solution of Boc-D-Ser-OH (1.5 g, 1 eq) in THF (54 mL) was added asolution of O-benzylhydroxylamine (1.3 eq) in THF (3 mL), H₂O (30 mL),and a solution of DCC (1.3 eq) in THF (3 mL). The solution was stirredat room temperature until analysis by LCMS indicated the startingmaterial had been consumed (1 hr), at which point the THF was evaporatedby rotary evaporation. EtOAc and water were added to the residue and theaqueous layer was extracted 3× with EtOAc and the combined organiclayers were evaporated. The crude residue was then taken up in a smallamount of EtOAc and filtered. The filtrate was diluted with EtOAc,washed with 5% citric acid, saturated NaHCO₃ and brine then dried oversodium sulfate and concentrated. The crude residue was purified via ISCOsilica gel chromatography (20% to 90% EtOAc in Hex, product eluted at˜90% EtOAc) to give pure Compound 8A (63% yield).

In a flame dried flask over activated 4 A molecular sieves under Ar, asolution of Compound 8A (1 eq) and triphenylphosphine (1.1 eq) inacetonitrile was treated with a solution of anhydrous CCl4 (10 eq) inanhydrous AcCN and a solution of triethylamine (1.2 eq) in anhydrousAcCN. The mixture was allowed to stir overnight, then was filteredthrough celite and concentrated. The crude material was purified by ISCOsilica gel chromatography (0 to 3% MeOH in DCM, product eluted at 2.9%)to give Compound 8B (62% yield).

To a solution of Compound 8B (1 eq) in MeOH under Ar atmosphere wasadded Raney Ni slurry in water. The solution was then put under anatmosphere of H₂ and allowed to stir at room temperature for 7 hrs oruntil TLC indicated complete consumption of starting material. Themixture was then filtered through celite and the filtrate wasconcentrated. The crude material was purified via ISCO silica gelchromatography (0 to 6% MeOH in DCM, product eluted at ˜1% MeOH) to giveCompound 8C (79% yield).

In a flame dried flask under Ar, a solution of Compound 8C (1 eq) inAcCN was heated to 50° C. The solution was then treated with cesiumcarbonate (1.2 eq) and methyl bromoacetate (1.5 eq). The mixture wasstirred at 50° C. until TLC indicated complete consumption of startingmaterials then the reaction was cooled and diluted with EtOAc and water.The aqueous layer was extracted 3× with EtOAc, then the combined organiclayers were washed with brine and dried over sodium sulfate andconcentrated. The crude material was purified via ISCO silica gelchromatography (0 to 10% MeOH in DCM, product eluted at 6.5% MeOH) togive Compound 8D (36% yield). ¹H NMR (CDCl₃) δ 7.35 (m, 5H), 5.41 (br s,1H), 5.112 (s, 2H), 4.61 (m, 1H), 3.84 (m, 1H), 3.81 (s, 3H).

Compound 8D was treated with a 5:1 mixture of DCM:TFA on an ice bath.After 2 hrs TLC indicated the complete consumption of starting materialand the solvents were evaporated. The crude was taken up in DCM andevaporated by rotary evaporation 3× to give crude Compound 8E which wasused without further purification.

Compound 258F was prepared using the procedures described in GeneralMethods 6-8 and Scheme XIX.

To a solution of Compound 8E (5 eq) and Compound 258F (1 eq) in DMF wasadded HATU (1.2 eq) and DIEA (8 eq) and the reaction mixture was stirredat room temperature. After 4 hrs, the mixture was diluted with water andEtOAc. The aqueous layer was extracted 3× with EtOAc then the combinedorganic layers were washed with water and brine, dried over sodiumsulfate and concentrated. The crude material was purified via ISCOsilica gel chromatography (0 to 12%, MeOH in DCM, product eluted at ˜8%MeOH) to give pure Compound 258G (49% yield). MS (ESI) m/z 1087.1(M+H)⁺.

To a solution of Compound 258G in EtOH under Ar was added 1 N HCl (1.9eq) 10% Pd/C (100% w/w). The mixture was then put under an atmosphere ofH₂ and allowed to stir for 4 hrs at which point TLC indicated completeconsumption of starting material. The mixture was filtered throughcelite and concentrated to give the Compound 258 as a bis-hydrochloridesalt. MS (ESI) m/z 819.3 (M+H)⁺.

Example 159

Compound 259F is prepared using the procedures described in GeneralMethods 6-8. MS (ESI) m/z 959.2 (M+H)⁺.

To a solution of Compound 259F (100 mg, 0.104 mmol), HATU (79.0 mg,0.208 mmol), and Compound 3F2 (40.4 mg, 0.156 mmol) in DCM (2.4 mL) andDMF (0.8 mL) at 0° C. was added DIEA (40.2 mg, 0.312 mmol). After 15-30min the reaction was allowed to warm 25° C. and stirred at 25° C. for 30min. After ELSD showed the reaction was complete, the mixture wasextracted with DCM (10 mL) and water (5 mL). The resulting mixture wasextracted with DCM (5 mL×2). The combined organic layers were washedwith diluted HCl (<0.1 M), then NaHCO₃ solution, brine. The solvent wasremoved and the residue was extracted with EtOAc (30-50 mL):water (10-15mL). The organic layers were washed water (10 mL), brine, dried overNa₂SO₄. The mixture was filtered and the filtrate was concentrated. Theresidue was crystallized from acetonitrile to give Compound 259G (90.0mg, yield: 74.3%). MS (ESI) m/z 1165.0 (M+H)⁺.

To a mixture of Compound 259G (190 mg, 0.163 mmol) in THF (2 mL) wasadded Pd/C (50.0 mg) and CH₃COOH (0.5 mL) under H₂. The mixture wasdegassed with H₂ three times before stirring at 25° C. at 50 psi H₂.After 12 hrs, LC-MS showed the reaction was completed. The catalyst wasfiltered and the solvent was evaporated, the crude residue was purifiedby prep-HPLC to give Compound 259H (120 mg, yield: 68.5%).

To a solution of Compound 259H (50.0 mg, 0.0466 mmol), HATU (35.4 mg,0.0932 mmol) and Compound 259B (29.2 mg, 0.0932 mmol) in DCM (0.5 mL)and DMF (0.5 mL) at 0° C. was added DIEA (18.1 mg, 0.140 mmol). Thereaction was stirred 2 hrs at 0° C. After LCMS showed the reaction wascomplete, DCM was evaporated. The crude residue was taken up in DMF andpurified by prep-HPLC to give Compound 259I (15.0 mg, yield: 23.4%).

To a mixture of Compound 259I (7.50 mg, 0.00548 mmol) in EtOAc (0.5 mL)was added Pd/C (10.0 mg) under H2. The mixture was degassed with H₂three times before stirring at 25° C. under 50 psi H₂. After 12 hrs,LC-MS showed the reaction was completed. Then the catalyst was filteredand the solvent was evaporated to give Compound 259J (5.0 mg, yield:76.8%).

A solution of Compound 259J (5.00 mg, 0.00421 mmol) in TFA:DCM:TES(50:45:5) (1 mL) was stirred at 25° C. for 1 hr, then TFA was evaporatedand ELSD showed the reaction was completed. The crude residue was takenup in DMSO and purified by prep-HPLC to give Compound 259 (3.0 mg,yield: 71%). MS (ESI) m/z 989.3 (M+H)⁺.

Example 160

To a solution of Compound 259H (50.0 mg, 0.0466 mmol), HATU (35.4 mg,0.0932 mmol), then D-Ala(O-tBu) (13.5 mg, 0.0932 mmol) in DCM (0.5 mL)and DMF (0.5 mL) at 0° C. was added DIEA (18.1 mg, 0.140 mmol). Thereaction was stirred 2 hrs at 0° C. After LCMS showed the reaction wascomplete and DCM was evaporated. The crude residue was taken up in DMFand purified by prep-HPLC to give Compound 260I (40.0 mg, yield: 71.6%).

To a solution of Compound 260I (40.0 mg, 0.0333 mmol) in TFA:DCM:TES(50:45:5) (1 mL), was stirred at 25° C. for 1 hr, then TFA wasevaporated and ELSD showed the reaction was completed. Then the cruderesidue was washed with petroleum ether to give Compound 260 (15.0 mg,yield: 47.6%). MS (ESI) m/z 945.6 (M+H)⁺.

Example 161

To a mixture of Compound 261F (10 mg, 0.00953 mmol) in EtOH (1.0 mL) wasadded PdCl₂ (0.2 mg,), Et₃N (0.1 mg, 0.000953 mmol), Et₃SiH (11.0 mg,0.095 mmol) under N₂. The mixture was stirred overnight. After LCMSshowed the reaction was complete, the solvent was removed and the cruderesidue was taken up in DMSO and purified by prep-HPLC to give Compound261 (3.0 mg, yield: 33%). MS (ESI) m/z 945.5.

Example 162

To a solution of triphosgene (47.7 mg, 0.162 mmol) in dry DCM (5.0 mL)was slowly added a solution of Compound 262A (110 mg, 0.487 mmol) andDIEA (0.503 g, 3.90 mmol) in THF (5.0 mL) at 0° C. The reaction mixturewas allowed to stir at 20° C. for 25 min. The solution of Compound 262A1was used to next step directly without purification.

Compound 129D2 was added to the solution of Compound 262A1 at 0° C. Thereaction mixture was warmed to 20° C. and was shaken at 20° C. for 4hrs. After ELSD showed the reaction was complete, the mixture wasfiltered. The filter cake was washed with THF (20.0 mL×3) and DCM (20.0mL×3) separately, and then dried. TFA/DCM (1%, 5.0 mL) was added and themixture was shaken at 20° C. for 5 min. The mixture was filtered and thefiltrate was treated with saturated NaHCO₃ solution until pH ˜7-8. Theaqueous layer was adjusted with citric acid until pH ˜3-4. The mixturewas extracted with DCM (20.0 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated to give a residue,which was purified by prep-HPLC to give Compound 262F (80.0 mg, yield:61.6%). MS (ESI) m/z 1083.3 (M+H)⁺.

Using the procedures described in General Methods 9 and 10, Compound 262was prepared from Compound 262F. MS (ESI) m/z 890.4 (M+H)⁺.

Example 163

To a solution of triphosgene (47.7 mg, 0.162 mmol) in dry DCM (5 mL) wasslowly added a solution of Compound 263A (110 mg, 0.487 mmol) and DIEA(0.500 g, 3.90 mmol) in THF (5 mL) at 0° C. The reaction mixture wasallowed to stir at 20° C. for 25 min. The solution of Compound 263A1 wasused directly in the next step without purification.

A solution of Compound 263A1 and Compound 129D2 was mixed at 0° C. inTHF (5 mL). The reaction mixture was warmed to 20° C. and was shaken at20° C. for 4 hrs. After ELSD showed the reaction was complete, themixture was filtered. The filter cake was washed with THF (20 mL×3) andDCM (20 mL×3) sequentially, and then dried. TFA/DCM (1%, 5 mL) was addedand the mixture was shaken at 20° C. for 5 min. Then the mixture wasfiltered and the filtrate was treated with saturated NaHCO₃ solutionuntil pH ˜7-8. The aqueous layer was adjusted with citric acid until pH˜3-4. The mixture was extracted with DCM (20 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated togive a residue, which was purified by prep-HPLC to give Compound 263F(80.0 mg, yield: 61.7%). MS (ESI) m/z 1082.4 (M+H)⁺.

Using the procedures described in General Methods 9 and 10, Compound 263was prepared from Compound 263F. MS (ESI) m/z 889.4 (M+H)⁺.

Example 164

A solution of Compound 263A1 (10.0 mL, approximately 0.480 mmol) andCompound 150D2 (prepared according to General Methods 5 and 6, 0.400 g,0.200 mmol) was stirred at 0° C. The reaction mixture was warmed to 20°C. and was shaken at 20° C. for 4 hrs. After ELSD showed the reactionwas completed, the mixture was filtered. The cake was washed with THF(20 mL×3) and DCM (20 mL×3) sequentially, and then dried. TFA/DCM (1%, 5mL) was added and the mixture was shaken at 20° C. for 5 min. Themixture was filtered and the filtrate was treated with saturated NaHCO₃solution until pH ˜7-8. The aqueous layer was adjusted with citric aciduntil pH ˜3-4. The mixture was extracted with DCM (20 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to give a residue, which was purified by prep-HPLC to giveCompound 264F (80.0 mg, yield: 42.0%). MS (ESI) m/z 954.5 (M+H)⁺.

Using the procedures described in General Methods 9, 10 and 11, Compound264 was prepared from Compound 264F.

Example 165

Using the procedures described in General Methods 9, 10 and 11, Compound265 was prepared from Compound 265F. MS (ESI) m/z 732.4 (M−H₂O+H)⁺.

Example 166

A solution of 1-bromo-4-butylbenzene (50.0 g, 0.333 mol),4-formylphenylboronic acid (47.2 g, 0.222 mol), Na₂CO₃ (70.6 g, 0.666mol) in toluene/THF/H₂O (200 mL/200 mL/200 mL) was degassed with N₂three times, then Pd(PPh₃)₄ (12.8 g, 11.2 mmol) was added. The resultingmixture was degassed with N₂ three times and then heated to reflux for 5hrs. After TLC showed the reaction was complete, toluene and THF wasremoved under vacuum. The residue was extracted with EA (30 mL×3). Thecombined organic layers were washed with brine, dried with Na₂SO₄. Thesolvent was removed to give the crude product. The crude product waspurified by column chromatography on silica gel eluted with PE. Thesolvent was removed to give Compound 266A1 (20.0 g, yield: 37.8%), as ayellow oil.

To a mixture of Compound 266A2 (0.8 g, 3.45 mmol) and Compound 266A1(0.862 g, 3.62 mmol) in DCM (2 mL) was added DIEA (0.31 g, 2.3 mmol) andNa₂SO₄. After stirring for 4 h, the mixture was filtered and thefiltrate was concentrated to give a residue. The residue was dissolvedin MeOH (5 ml) and NaBH₄ (144 mg, 3.79 mmol) was added at 0° C. Themixture was warmed to 26° C. After 2 h, TLC (PE/EA=1/1, R_(f)=0.1)showed the reaction was complete. The reaction was quenched with water(1 mL), concentrated and purified by column chromatography (PE/EA=1:1)give Compound 266A3 (2 g, crude). MS (ESI) m/z 455.1 (M+H)⁺.

To a mixture of Compound 266A3 (1.60 g, crude) in MeOH (2 ml) was addedBoc₂O (900 mg, 4.13 mmol). The mixture was stirred at 24° C. for 12 h.TLC (PE/EA=1/1, R_(f)=0.5) showed the reaction was completed. Thesolvent was concentrated to give a residue which was purified by columnchromatography (PE/EA=1:1) to give Compound 266A4 (1.30 g, 66.7%) ascolorless oil. MS (ESI) m/z 577.0 (M+Na)⁺.

To a mixture of Compound 266A4 (1.30 g, 2.35 mmol) in THF (5 mL) wasadded LiOH (0.296 g, 7.04 mmol) in H₂O (5 ml). The reaction was stirredat 30° C. for 36 h. TLC (PE/EA=1/1, R_(f)=0.6) showed the reaction wascompleted. The solvent was acidified to pH ˜3-4 with 1N HCl, extractedwith DCM (20.0 ml×4). The organic layer were dried, filtered andconcentrated to give Compound 266A5 (0.9 g, 70.9%) as yellow oil. MS(ESI) m/z 563.3 (M+Na)⁺.

Using Compound 266A5 and the procedures described in General Methods 6-8and Scheme XIX, Compound 266F was prepared. MS (ESI) m/z 997.6 (M+H)⁺.

Using the procedures described in General Methods 9 and 10, Compound 266was prepared from Compound 266F. MS (ESI) m/z 846.4 (M+H)⁺.

Example 167

Using the procedure described in General Procedure 11, Compound 267 wasprepared from Compound 266. MS (ESI) m/z 694.3 (M−H₂O+H)⁺.

Example 168

Using the procedures described in General Methods 6-8 and Scheme XIX,Compound 268F was prepared. MS (ESI) m/z 923.1 (M+H)⁺. Using theprocedures described in General Methods 9 and 10, Compound 268 wasprepared from Compound 268F. MS (ESI) m/z 872.3 (M+H)⁺.

Example 169

Using the procedures described in General Methods 6-8 and Scheme XIX,Compound 269F was prepared. MS (ESI) m/z 923.2 (M+H)⁺. MS (ESI) m/z923.1 (M+H)⁺. Using the procedures described in General Methods 9 and10, Compound 269 was prepared from Compound 269F. MS (ESI) m/z 872.1(M+H)⁺.

Example 170

To a mixture of Compound 266A1 (0.5 g, 2 mmol) and methyl3-aminopropanoate (0.3 g, 2.2 mmol) in DCM (2 ml) was added DIEA (0.3 g,2.3 mmol) and Na₂SO₄. After stirring for 4 h, the mixture was filteredand the filtrate was concentrated. The residue was dissolved in MeOH (5ml) and NaBH₄ (84 mg, 2.2 mmol) was added to the solution at 0° C. Themixture was warmed to room temperature. After 2 h, TLC (PE/EA=10/1,R_(f)=0.1) showed the reaction was complete. The reaction was quenchedby water (1 mL), concentrated to give a solid (0.7 g, crude) used in thenext step without further purification. This material was treated withBoc₂O (0.5 g, 2.3 mmol) in MeOH (5 mL) was stirred at 26° C. for 5 h.TLC (DCM/MeOH=10/1, R_(f)=0.7) showed the reaction was complete. Thesolvent was concentrated to get a residue, which purified by columnchromatography (PE) to give Compound 270A2 (0.65 g, 73%) as a colorlessoil. MS (ESI) m/z 448.2 (M+Na)⁺.

To a mixture of Compound 270A2 (0.68 g, 2 mmol) in THF (5 ml) was addedLiOH (96 mg, 2.3 mmol) in water (5 mL). The mixture was stirred at 26°C. for 2 h. TLC (PE/EA=5/1, R_(f)=0.1) showed the reaction was complete.Volatiles were removed in vacuo and the aqueous mixture was acidified topH=3˜4 with 0.3N HCl and extracted with DCM (20 ml×3). The organic layerwere dried, filtered and concentrated to give Compound 270A3 (0.4 g,84%) as a white solid.

Using the procedures described in General Methods 6-8 and Scheme XIX,Compound 270F was prepared from Compound 270A3. MS (ESI) m/z 890.5(M+Na)⁺. Using the procedures described in General Methods 9 and 10,Compound 270 was prepared from Compound 270F. MS (ESI) m/z 817.7 (M+H)⁺.

Example 171

To a mixture of Compound 266A1 (0.5 g, 2 mmol) and methyl3-aminobutanoate (0.34 g, 2.2 mmol) in DCM (2 ml) was added DIEA (0.31g, 2.3 mmol) and Na₂SO₄. After stirring for 4 h, the mixture wasfiltered and the filtrate was concentrated to get a residue, whichdissolved in MeOH (5 ml). NaBH₄ (84 mg, 2.2 mmol) was added to it at 0°C. Then the mixture was warmed to 26° C. After 2 h, TLC (PE/EA=10/1,R_(f)=0.1) showed the reaction was complete. The reaction was quenchedby water (1 ml), concentrated to give a solid (0.7 g, crude) used in thenext step without further purification. This material was treated withBoc₂O (0.5 g, 2.3 mmol) in MeOH (5 ml) was stirred at room temperaturefor 5 h. TLC (DCM/MeOH=10/1, R_(f)=0.7) showed the reaction wascomplete. The solvent was concentrated to get a residue, which waspurified by column chromatography (petroleum ether) to give Compound271A2 (0.45 g, 73%) as a colorless oil. MS (ESI) m/z 462.1 (M+Na)⁺.

To a mixture of Compound 270A2 (0.45 g, 2 mmol) in THF (5 ml) was addedLiOH (96 mg, 2.3 mmol) in water (5 ml). The mixture was stirred roomtemperature for 2 h. TLC (PE/EA=5/1, R_(f)=0.1) showed the reaction wascomplete. Volatiles were removed in vacuo and the aqueous mixture wasacidified to pH=3˜4 with 0.3N HCl, extracted with DCM (20 ml×3). Theorganic layer was dried, filtered and concentrated to give Compound271A3 (0.4 g, 84%) as white solid.

Using the procedures described in General Methods 6-8 and Scheme XIX,Compound 271F was prepared from Compound 271A3. MS (ESI) m/z 881.8(M+Na)⁺. Using the procedures described in General Methods 9 and 10,Compound 271 was prepared from Compound 271F. MS (ESI) m/z 831.8 (M+H)⁺.

Example 172

Compound 272F was prepared using the procedures described in GeneralMethods 6-8 and Scheme XIX, Compound 272F. MS (ESI) m/z 822.5 (M+Na)⁺.Using the procedures described in General Methods 9 and 10, Compound 271was prepared from Compound 271F. MS (ESI) m/z 831.8 (M+H)⁺.

Example 173

To a mixture of Compound 266A1 (1.10 g, 4.62 mmol) in dry DCM (20 mL)was added Compound 273A (0.762 g, 4.85 mmol), DIEA (0.686 g, 5.32 mmol)and Na₂SO₄ at 24° C. The mixture was stirred for 2 hrs at 24° C. Themixture was filtered and the filtrate was evaporated. The residue wasdissolved in dry MeOH (10 mL), cooled to 0° C., and then NaBH₄ (184 mg,4.85 mmol) was added portion-wise. The mixture was stirred at 24° C. for2 hrs. After LCMS showed the reaction was complete, MeOH was evaporated.The crude product was purified by chromatography on gel silica, then themixture was in EA/HCl for 3 mins and evaporated. The solid was washedwith EA to give the pure product Compound 273A1 (450 mg, yield: 25.7%).

To a solution of Compound 273A1 (450 mg, 1.19 mmol) in THF/H₂O (10 mL/2mL) was added LiOH.H₂O (100 mg, 2.37 mmol) at 21° C. The mixture wasstirred overnight at 21° C. After TLC showed the reaction was complete,THF was evaporated and the mixture was extracted with EA. 1N HCl wasadded 1N HCl to the aqueous layer until pH to ˜3-4. The mixture wasextracted with EA, the organic layers were combined, dried with Na₂SO₄,filtered and concentrated to give the Compound 273A2 (260 mg, yield:62.2%).

Using the procedures described in General Methods 6-8 and Scheme XIX,Compound 273F was prepared from Compound 273A2. MS (ESI) m/z 808.2(M+Na)⁺. Using the procedures described in General Methods 9 and 10,Compound 273 was prepared from Compound 273F. MS (ESI) m/z 857.3 (M+H)⁺.

Example 174

To a solution of Compound 274A1 (1.00 g, 2.47 mmol), Compound 266A1 (679mg, 2.85 mmol) and DIEA (719 mg, 5.57 mmol) in dry DCM (50 mL) was addedNa₂SO₄ (10 g). The mixture was stirred at 25° C. for 4 hrs, filtered andthe filtrate was evaporated. To the residue was added dry MeOH (50 mL)and NaBH₄ (108 mg, 2.84 mmol) at 0° C. The reaction mixture was stirredat 25° C. for 30 mins. After LCMS showed the reaction was completed, 1 NHCl was added until pH to ˜7. The solution was evaporated to giveCompound 274A2 (1.00 g, yield: 68.4%) as light yellow solid. MS (ESI)m/z 591.9 (M+H)+.

To a solution of Compound 274A2 (1.00 g, 1.69 mmol) in dry MeOH (20 mL)was added 1N HCl until pH to ˜6-7, followed by addition of DIEA until pHto ˜7-8. To the mixture was added Boc₂O (0.732 g, 3.39 mmol) at 24° C.The mixture was stirred overnight at 24° C. After LCMS showed thereaction was complete, MeOH was evaporated and the crude product waspurified by chromatography on gel silica (PE:EA=15:1) to give Compound274A3 (0.680 g, yield: 58.3%). MS (ESI) m/z 713.4 (M+Na)⁺.

To a solution of Compound 274A3 (0.680 g, 0.985 mmol) in THF/H₂O (10mL/3 mL) was added LiOH.H₂O (0.166 g, 3.94 mmol) at 24° C. The mixturewas stirred overnight at 24° C. After TLC showed the reaction wascomplete, THF was evaporated. The mixture was extracted with PE and H₂O.To the aqueous layer was added 1N HCl until the pH to ˜4-5. The aqueousmixture was extracted with EA (10 mL×3). The organic layers werecombined, dried with Na₂SO₄ and concentrated to give Compound 274A4(0.400 g, yield: 89.3%).

To a solution of Compound 274A4 (0.400 g, 0.880 mmol) in DCM (15 mL) wasadded Boc₂O (0.228 g, 1.06 mmol) and Et₃N (0.267 g, 2.64 mmol) at 24° C.The mixture was stirred for 2 hrs at 24° C. After LCMS showed thereaction was complete, DCM was evaporated. The crude product was washedwith PE. The PE layer was evaporated to give Compound 274A5 (380 mg,77.9%).

Using the procedures described in General Methods 6-8 and Scheme XIX,Compound 274F was prepared from Compound 274A5. MS (ESI) m/z 1011.2(M+Na)⁺. Using the procedures described in General Methods 9 and 10,Compound 274 was prepared from Compound 274F. MS (ESI) m/z 860.2 (M+H)⁺.

Example 175

To a solution of Compound 274A3 (1.00 g, 1.69 mmol) in MeOH (50.0 mL)was added Boc₂O (527 mg, 2.44 mmol). The reaction was stirred at 25° C.for 4 hrs. After LCMS showed the reaction was completed, the solvent wasevaporated and the residue purified by silica-gel column chromatographyto give Compound 275A4 (0.580 g, yield: 49.7%) as a white solid.

To a solution of Compound 275A4 (0.580 g, 0.840 mmol) in DCE (20.0 mL)was added Me₃SnOH (1.18 g, 6.50 mmol). The reaction was stirred at 70°C. for 4 hrs. After LCMS showed the reaction was completed, the mixturewas cooled to 0° C. and treated with 1 M NaH₂PO₄ (60.0 mL). The mixturewas extracted with DCM (30.0 mL×2). The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated to give the crudeproduct. The crude product was purified by silica-gel columnchromatography to give Compound 275A5 (0.550 g, yield: 96.4%) as whitesolid. MS (ESI) m/z 699.0 (M+Na)⁺.

Using the procedures described in General Methods 6-8 and Scheme XIX,Compound 275F was prepared from Compound 275A5. MS (ESI) m/z 953.1(M+Na)⁺. Using the procedures described in General Methods 9 and 10,Compound 275 was prepared from Compound 275F. MS (ESI) m/z 902.4 (M+H)⁺.

Example 176

Using the procedures described in Example 174, Compound 276A5 wasprepared from Compound 276A1. Using the procedures described in GeneralMethods 6-8 and Scheme XIX, Compound 276F was prepared from Compound276A5. MS (ESI) m/z 997.2 (M+Na)⁺. Using the procedures described inGeneral Methods 9 and 10, Compound 276 was prepared from Compound 276F.MS (ESI) m/z 846.2 (M+H)⁺.

Example 177

Using the procedures described in Examples 174 and 175, Compound 277A5was prepared from Compound 277A1. MS (ESI) m/z 663.1 (M+H)⁺. Using theprocedures described in General Methods 6-8 and Scheme XIX, Compound277F was prepared from Compound 277A5. MS (ESI) m/z 939.5 (M+Na)⁺. Usingthe procedures described in General Methods 9 and 10, Compound 277 wasprepared from Compound 277F. MS (ESI) m/z 888.2 (M+H)⁺.

Example 178

To a solution of Compound 278A1 (1.00 g, 2.39 mmol),4-(4-butylphenyl)benzoic acid (0.728 g, 2.89 mmol) and NaHCO₃ (0.742 g,8.84 mmol) in dry THF (30 mL) and DMF (30 mL) was added HATU (1.09 g,2.89 mmol). The mixture was stirred at 25° C. until LCMS indicated thereaction was finished (5 hrs). THF was evaporated and the mixture waspoured into water (100 mL) and extracted with DCM (80 mL×2). Thecombined organic layers were evaporated and purified by silica-gelcolumn chromatography to give Compound 278A2 (800 mg, yield: 54.4%).

A mixture of Compound 278A2 (800 mg, 1.29 mmol) and LiOH (108 mg, 2.58mmol) in THF/H₂O (30 mL/10 mL) was stirred at 10° C. LCMS showed thereaction was complete after 2 hrs, at which time the THF was evaporated.The mixture was extracted with PE (30 mL×3), the aqueous layers wereadjusted to pH ˜3-4 with 1 N HCl solution. The resulting mixture wasfiltered and the cake was washed with water and dried to give Compound278A3 (400 mg, yield: 91.0%), as a white solid.

To a mixture of Compound 278A3 (400 mg, 1.05 mmol) in THF/H₂O (100mL/100 mL) was added NaHCO₃ (176 mg, 2.10 mmol). The mixture was cooledto 0° C. and a solution of Fmoc-OSu (354 mg, 1.05 mmol) in THF (100 mL)was added dropwise over 8 hrs. After stirring for an additional 2 hrs at10° C., LCMS showed the reaction was complete and the THF wasevaporated. The mixture was extracted with PE (30 mL×3) and the aqueouslayers were adjusted to pH ˜4-5 with 1 N HCl solution. The resultingmixture was filtered and the filter cake was washed with water and driedto give Compound 278A4 (600 mg, yield: 94.9%), as a white solid. MS(ESI) m/z 605.1 (M+H)⁺.

Using the procedures described in General Methods 6-8 and Scheme XIX,Compound 278F was prepared from Compound 278A4. MS (ESI) m/z 1104.1(M+H)⁺.

To a solution of Compound 278F (200 mg, 0.181 mmol), HATU (138 mg, 0.362mmol), and 3F2 (70.3 mg, 0.272 mmol) in DCM (2.4 mL) and DMF (0.8 mL)was added DIEA (70.0 mg, 0.543 mmol). After 15-30 mins the reaction wasallowed to warm to 15° C. and stirred for 30 mins. After LCMS showed thereaction was complete, water (1 mL) was added and the mixture wasfiltrated, the filter cake was washed with water and petrol ether toafford Compound 278G as a crude product (180 mg, yield: 75.9%).

To a mixture of Compound 278G (160 mg, 0.122 mmol) in CH₃CN (5 mL) wasadded Et₂NH (26.7 mg, 0.366 mmol). The mixture was stirred at 10° C. for17 hrs. After LCMS showed the reaction was completed, CH₃CN was removed.The residue was dissolved in MeOH and purified by prep-HPLC to giveCompound 278H (50.0 mg, yield: 37.7%).

A solution of Compound 278H (25.0 mg, 0.0230 mmol) in TFA:DCM:TES(50:45:5) (1 mL) was stirred at 10° C. for 20 mins, then TFA wasevaporated and LCMS showed the reaction was completed. The crude residuewas dissolved in MeOH and purified by prep-HPLC to give Compound 278(5.60 mg, yield: 27.5%). MS (ESI) m/z 887.6 (M+H)⁺.

Example 179

Using the procedure described in General Methods 10 for the preparationof the boronate esters, the boronate ester Compound 279 was preparedfrom Compound 279G (1.5 mg, yield: 18.3%). MS (ESI) m/z 929.2 (M+H)⁺.

Biological Data Example 180

Determination of Minimum Inhibitory Concentration—Method A

In vitro antimicrobial activity of each compound was determined bymeasuring minimal inhibitor concentrations (MICs) using the brothmicro-dilution technique as approved by the Clinical and LaboratoryStandards Institute (CLSI). Antibacterial activity was measure againsttwo strains of bacteria: 1) Methicillin Resistant Staphylococcus aureusstrain USA 300 (NRS384) and 2) a strain of Escherichia coli MC4100IMP-4213 in which transcription of the SPase encoding gene has beenplaced under the control of a tetracycline inducible promoter in orderto decrease SPase expression levels. Cells were inoculated ontoTrypyticase Soy Agar or Luria Agar containing 16 ng/ml ofanhydrotetracycline respectively and grown at 35° C. for 20 hours.Inocula suspensions were made by scraping cells into 1 mL of testingmedia (cation adjusted Mueller Hinton Broth supplemented with 0.002% v/vTween-80) and diluting to a final OD_(600nm) of 0.01.

Test compounds were prepared in DMSO at a concentration of 10 mg/ml.These compound stocks were diluted into testing media at a concentrationof 64 μg/ml and 9 serial 1:2 dilutions were made in the same media, in96-well U bottom microtiter dishes. Inocula suspensions were added tothe two fold serial dilutions of test compounds to a final density of ODOD_(600nm) of 0.0005 and incubated stationary at 35° C. for 22 hours,after which the plates were examined visually. The MICs were recorded asthe lowest concentration of test compound that completely preventedbacterial growth. The results are listed in Table 1.

TABLE 1 Antimicrobial activities in whole cell bacterial assays MIC MIC(μg/mL) (μg/mL) Compound E. coli S. aureus 108 >64 64 103 ND >64 104 ND8 105 >64 >64 110 >64 >64 123 25 64 109 >64 >64 128 >64 >64 111 >64 >64122 >64 40 112 >64 >64 124 >64 >64 102 >64 >64 101 >64 >64 113 ND ND 125ND ND 114 ND ND 117 >64 >64 116 >64 >64 115 >64 >64 118 11 0.71 127 1.616 126 1.4 16 119 >64 >64 120 32 >64 121 0.5 0.25 ND = not determined

Determination of Minimum Inhibitory Concentration—Method B

In vitro antimicrobial activity of each compound was determined bymeasuring minimal inhibitor concentrations (MICs) using the brothmicro-dilution technique as approved by the Clinical and LaboratoryStandards Institute (CLSI). Antibacterial activity was measure againsttwo strains of bacteria: 1) methicillin resistant Staphylococcus aureus(MRSA) strain USA300 (NRS384) and 2) Escherichia coli strain MC4100IMP-4213, which harbors an LptD mutation. Bacterial inocula wereprepared by scraping cells into 1 mL of testing media (cation adjustedMueller Hinton Broth supplemented with 0.002% v/v Tween-80) and dilutingto a final OD_(600nm) of 0.01.

Test compounds were prepared in DMSO at a concentration of 10 mg/ml.These compound stocks were diluted into testing media at a concentrationof 64 μg/ml and 9 serial 1:2 dilutions were made in the same media, in96-well U bottom microtiter dishes. Bacterial inocula were added to thetwo fold serial dilutions of test compounds to a final density of ODOD_(600nm) of 0.0005 and incubated stationarily at 35° C. for 22 hours,after which the plates were examined visually. The MICs were recorded asthe lowest concentration of test compound that completely preventedbacterial growth. The results are listed in Table 2.

TABLE 2 Antimicrobial activities in whole cell bacterial assays MIC MICMIC MIC (μg/mL) (μg/mL) (μg/mL) (μg/mL) Compound E. coli S. aureusCompound E. coli S. aureus 129 0.91 0.74 130 11 64 131 0.44 0.45 132 10.21 133 0.79 1.4 134 1.4 0.87 135 16 3.2 136 1 1.4 137 23 16 138 >64 5139 2 1 140 8 1 141 5.7 0.79 142 0.5 0.22 143 5.7 0.35 144 0.25 0.25 1455 3.2 146 0.25 0.4 147 0.31 0.25 148 0.4 0.23 149 0.31 0.28 150 0.5 0.3151 1.2 0.71 152 0.5 0.4 154 32 2.8 155 ND ND 156 0.5 0.31 157 4 2 158 55.7 159 16 1 160 64 2.8 161 0.71 0.63 162 0.5 0.4 163 >64 4 164 1 1.4165 0.63 0.63 166 0.5 0.63 167 4 1.7 168 1 0.79 169 11 3.2 170 0.4 2 1710.25 0.71 172 8 8 173 2 2 174 0.5 0.25 175 2 1.2 176 8 16 177 2 2 1780.25 0.063 179 0.5 2 180 1 1 181 0.5 0.4 182 0.71 4 183 1 1 184 0.130.25 185 0.71 4 186 0.13 0.13 187 2.8 8 188 8 16 189 64 >64 190 >64 64191 16 20 192 16 0.59 193 5 0.16 194 6.3 0.71 195 32 1.2 196 2.5 0.66197 1 0.3 198 5 0.5 199 >64 7 200 64 >64 201 64 4.6 202 23 1.1 203 321.4 204 4.6 0.45 205 32 2 206 2 0.5 207 2 0.099 208 4 0.31 209 2.5 1 2104 0.71 211 32 0.71 212 5 0.84 213 1.3 0.22 214 5.7 0.35 215 4 0.5 216 40.21 217 1.6 0.35 218 1.3 0.5 219 64 5 220 4 0.5 221 8 1 222 2 1.4 223ND ND 224 2.8 0.13 225 2 0.57 226 25 2.8 227 13 8 228 2.8 5.7 229 32 64230 20 2 231 0.5 0.5 232 0.25 0.31 233 1 0.5 234 0.5 0.4 235 0.5 0.25236 8 2 237 2 0.71 238 0.35 0.35 239 2 0.71 240 4 0.71 241 0.18 0.25 24211 1.4 243 2 0.5 244 64 45 245 0.5 0.35 246 64 23 247 0.5 0.5 248 0.250.25 249 1 0.35 250 0.71 0.35 251 >64 3.4 252 >64 5 253 11 8 254 11 8255 ND ND 256 ND ND 257 ND ND 258 23 >64 259 4 11 260 1 4 261 0.79 0.71262 8 2.8 263 2 0.71 264 ND ND 265 4 0.13 266 1 0.5 267 0.25 0.13 268 161 269 8 0.5 270 8 0.5 271 11 0.5 272 32 0.71 273 8 0.088 274 16 0.13 27532 1 276 16 0.5 277 32 0.5 278 16 4 279 8 11 ND = not determined

Enzyme Inhibition Assay

Full length His-tagged E. coli SPase proteins were expressed in E. coliBL21(DE3) containing the plasmid pET23-lepB. Briefly, saturatedovernight cultures grown in 20 ml of Luria-Bertani medium supplementedwith ampicillin were subcultures into 1.5 L of Luria-Bertani, and shakenat 37° C. until an optical density at 600 nm of 0.4-0.5 was achieved.Protein expression was induced with Isopropylβ-D-1-thiogalactopyranoside (ITPG) at a final concentration of 0.5 μM,and purified using nickel affinity chromatography.

Full length His-tagged S. aureus SPase protein was expressed similarlyfrom E. coli BL21(DE3) containing the plasmid pCDF1-SaSpsB and purifiedsimilarly to the E. coli protein with the following exceptions. SPaseprotein was solubilized using 300 mM NaCl, 20 mM Tris pH 8.06, 5 mMImidazole, 10% glycerol, 1% Triton X-100, prior to purification inNi-NTA Superflow resin and resin bound protein was washed in a similarbuffer containing 1% Elugent in place of Triton X-100 prior to proteineluted in wash buffer supplemented with 300 mM imidazole. Protein puritywas judged to exceed 95% by visual inspection of SDS-PAGE followed byComassie staining. All protein concentrations were determined by BCAassay.

Signal peptidase enzyme activity of the above proteins was measuredusing two fluorogenic peptide substrates (decanoyl-LS SPAYNO2A

ADKabzPD (SEQ ID NO:1) and decanyol-LTPTAYNO2A

ASKKabzDD) (SEQ ID NO:2), where abz is the fluorescence donor2-aminobenzamide, YNO2 is the fluorescence acceptor 3-nitrotyrosine, andthe cleavage site is indicated with an arrow. Enzyme mix solution wasprepared by diluting 2.5 nM of Escherichia coli or Staphylococcus aureusSPase protein into reaction buffers consisting of 20 mM PO4 pH 7.4, 100mM NaCl, and 1% Elugent™ or octyl phenoxypolyethoxylethanol detergent ata concentration of 0.25% or 0.0625%. Reactions were initiated by theaddition of substrate to a final concentration of 20 μM. Reactionprogress was monitored by measuring the increase in fluorescence signal(excitation at 314 nm, emission at 416 nm) using a SpectraMax M2fluorescence microplate reader. To determine IC50 values of testcompounds, compound stock solutions were prepared in DMSO at aconcentration of 1 mM. Three-folder serial dilutions of test compounds,starting at 10 μM, were prepared in enzyme mix solution and incubated atroom temperature for 10 minutes. Following this incubation, fluorogenicsubstrate was added to a final concentration of 20 μM and the increasein fluorescence, corresponding to substrate cleavage, was monitoredcontinuously at room temperature for 1 hour. Initial reaction rates werecalculated based on the rate of increase in fluorescence during thereaction. Reaction rates were plotted as a function of compoundconcentration, and IC₅₀ values are determined nonlinear regressionanalysis (SoftMaxPro 5.4, Molecular Devices™) of the sigmoidaldose-response curve. The results are listed in Table 3.

TABLE 3 Inhibitory activities (IC50) in biochemical SPase activityassays IC 50 IC 50 IC 50 IC 50 (nM) (nM) (nM) (nM) Compound E. coli S.aureus Compound E. coli S. aureus 101 11000 86 102 18000 9.7 103 11000110 104 8900 18 105 ND ND 108 20000 2100 109 50000 4900 110 ND 150 1114900 18000 112 31000 3400 113 50000 470 114 50000 390 115 1000 170 116310 38 117 300 350 118 1100 9.4 119 290 59 120 1600 100 121 ND ND 1221500 7.6 123 220 42 124 810 83 125 730 55 126 17 6 127 12 3.7 128 3000670 129 14 140 130 1000 530 131 19 98 132 24 77 133 15 170 134 8.7 120135 31 25 136 14 39 137 1200 26000 138 1000 1100 139 3.4 8.5 140 50 52141 33 23 142 15 34 143 250 180 144 18 36 145 39 240 146 12 160 147 1498 148 7.4 140 149 3.9 129 150 6 270 151 8.8 38 152 25 350 154 14 8.1155 39 250 156 5.5 97 157 130 1000 158 33 400 159 240 86 160 2100 900161 60 300 162 12 200 163 240 310 164 44 120 165 120 410 166 36 350 1675.2 190 168 5.4 250 169 3.9 87 170 10 530 171 27 520 172 20 750 173 69550 174 59 130 175 5.5 110 176 56 1200 177 70 640 178 3.1 58 179 22 570180 11 280 181 5.4 18 182 35 1100 183 20 610 184 5.9 300 185 41 580 1866.9 370 187 170 2100 188 120 2900 189 430 7700 190 1300 64000 191 3800050000 192 27 12 193 15 3 194 16 4.7 195 19 2.6 196 8.8 5.7 197 11 6.2198 42 8.9 199 4.5 1.4 200 5200 1200 201 8 1.9 202 7.1 3.5 203 130 21204 33 13 205 210 20 206 6.3 5.2 207 87 13 208 20 5.7 209 12 15 210 5616 211 50000 36 212 26 12 213 6.8 7.7 214 77 17 215 77 17 216 29 4.1 21715 14 218 6.9 13 219 560 46 220 36 7 221 62 130 222 6.6 24 223 ND ND 22455 12 225 7.1 4 226 440 140 227 550 850 228 360 270 229 290 220 230 390150 231 4.5 95 232 5 140 233 29 220 234 8.3 53 235 21 50 236 28 130 23716 210 238 4.6 33 239 17 670 240 28 88 241 2.1 42 242 21 54 243 10 80244 350 1100 245 8.7 130 246 55 290 247 17 110 248 11 170 249 17 160 2508.4 110 251 9200 18 252 3000 8.7 253 4800 2100 254 1200 660 255 ND ND256 ND ND 257 ND ND 258 50000 50000 259 2.6 32 260 5.6 83 261 41 280 26237 15 263 88 72 264 ND ND 265 120 17 266 22 160 267 11 33 268 1600 81269 1800 340 270 650 120 271 200 16 272 1300 50 273 470 9.8 274 1700 35275 1500 110 276 2000 110 277 680 110 278 800 2300 279 530 7400 ND = notdetermined

Example 181 Clinical Trial of the Safety and Efficacy of Compounds ofFormula (I), (I′), (II), (II′), (III), or (III′) in Patients with C.Difficile-Associated Diarrhea

Purpose:

This study aims to determine the safety and efficacy of compoundspresented herein for the treatment of symptoms of C.difficile-associated diarrhea and lowering the risk of repeat episodesof diarrhea. The compounds are evaluated in comparison to currentstandard antibiotic treatment, so all patients will receive activemedication. All study-related care is provided including doctor visits,physical exams, laboratory tests and study medication. Total length ofparticipation is approximately 10 weeks.

Patients:

Eligible subjects will be men and women 18 years and older.

Criteria:

Inclusion Criteria:

-   -   Be at least 18 years old;    -   Have active mild to moderate C. difficile-Associated Diarrhea        (CDAD);    -   Be able to tolerate oral medication;    -   Not be pregnant or breast-feeding; and    -   Sign and date an informed consent form.

Study Design:

This is a randomized, double-blind, active control study of theefficacy, safety, and tolerability of a compound of Formula (I), (I′),(II), (II′), (III), or (III′) in patients with C. difficile-associateddiarrhea.

Example 182 Clinical Trial Comparing a Compound of Formula (I), (I′),(II), (II′), (III), or (III′) with Vancomycin for the Treatment of MRSAOsteomyleitis

Purpose:

This study aims to determine the efficacy of compounds presented hereinas compared to vancomycin for the treatment of methicillin-resistantStaphylococcus aureus (MRSA) osteomyelitis.

Patients:

Eligible subjects will be men and women 18 years and older.

Criteria:

Inclusion Criteria:

-   -   Culture-proven MRSA, obtained in operating room or sterile        biopsy procedure from bone site. The infection and sampling site        is either within the bone or a deep soft-tissue site that is        contiguous with bone; OR radiographic abnormality consistent        with osteomyelitis in conjunction with a positive blood culture        for MRSA;    -   Surgical debridement of infection site, as needed;    -   Subject is capable of providing written informed consent; and    -   Subject capable of receiving outpatient parenteral therapy for        12 weeks.

Exclusion Criteria:

-   -   Hypersensitivity to a compound of Formula (I), (I′), (II),        (II′), (III), or (III′) or vancomycin;    -   S. aureus resistant to a compound of Formula (I), (I′), (II),        (II′), (III), or (III′) or vancomycin;    -   Osteomyelitis that develops directly from a chronic, open wound;    -   Polymicrobial culture (the only exception is if        coagulase-negative staphylococcus is present in the culture and        the clinical assessment is that it is a contaminant);    -   Subject has a positive pregnancy test at study enrollment;    -   Baseline renal or hepatic insufficiency that would preclude        administration of study drugs;    -   Active injection drug use without safe conditions to administer        intravenous antibiotics for 3 months; and    -   Anticipated use of antibiotics for greater than 14 days for an        infection other than osteomyelitis.

Study Design:

This is a randomized, open-label, active control, efficacy trialcomparing vancomycin with a compound of Formula (I), (I′), (II), (II′),(III), or (III′) for the treatment of MRSA Osteomyelitis.

Example 183 Clinical Trial Evaluating a Compound of Formula (I), (I′),(II), (II′), (III), or (III′) in Selected Serious Infections Caused byVancomycin-Resistant Enterococcus (VRE)

Purpose:

This study aims to determine the safety and efficacy of a compound ofFormula (I), (I′), (II), (II′), (III), or (III′) in the treatment ofselected serious infections caused by VRE.

Patients:

Eligible subjects will be men and women 18 years and older.

Criteria:

Inclusion Criteria:

-   -   Isolation of one of the following multi-antibiotic resistant        bacteria: vancomycin-resistant Enterococcus faecium,        vancomycin-resistant Enterococcus faecalis alone or as part of a        polymicrobial infection; and    -   Have a confirmed diagnosis of a serious infection (eg,        bacteremia [unless due to an excluded infection], complicated        intra-abdominal infection, complicated skin and skin structure        infection, or pneumonia) requiring administration of        intravenous (IV) antibiotic therapy.

Exclusion Criteria:

-   -   Subjects with any concomitant condition or taking any        concomitant medication that, in the opinion of the investigator,        could preclude an evaluation of a response or make it unlikely        that the contemplated course of therapy or follow-up assessment        will be completed or that will substantially increase the risk        associated with the subject's participation in this study.        Anticipated length of antibiotic therapy less than 7 days

Study Design:

This is a randomized, double-blind, safety and efficacy study of acompound of Formula (I), (I′), (II), (II′), (III), or (III′) in thetreatment of selected serious infections caused by VRE.

Pharmaceutical Compositions

Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a compound of Formula (I), (I′),(II), (II′), (III), or (III′) is dissolved in DMSO and then mixed with10 mL of 0.9% sterile saline. The mixture is incorporated into a dosageunit form suitable for administration by injection.

In another embodiment, the following ingredients are mixed to form aninjectable formulation:

Ingredient Amount Compound of Formula (I), (I′), (II), 1.2 g (II′),(III), or (III′) sodium acetate buffer solution (0.4M) 2.0 mL HCl (1N)or NaOH (1M) q.s. to suitable pH water (distilled, sterile) q.s. to 20mL

All of the above ingredients, except water, are combined and stirred andif necessary, with slight heating if necessary. A sufficient quantity ofwater is then added.

Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (I), (I′), (II), (II′), (III), or (III′) is mixedwith 750 mg of starch. The mixture is incorporated into an oral dosageunit, such as a hard gelatin capsule, which is suitable for oraladministration.

In another embodiment, the following ingredients are mixed intimatelyand pressed into single scored tablets.

Ingredient Quantity per tablet, mg compound of Formula (I), (I′), (II),200 (II′), (III), or (III′) Cornstarch 50 croscarmellose sodium 25Lactose 120 magnesium stearate 5

In yet another embodiment, the following ingredients are mixedintimately and loaded into a hard-shell gelatin capsule.

Ingredient Quantity per tablet, mg compound of Formula (I), (I′), (II),200 (II′), (III), or (III′) lactose, spray-dried 148 magnesium stearate2

In yet another embodiment, the following ingredients are mixed to form asolution/suspension for oral administration:

Ingredient Amount Compound of Formula (I), (I′), (II), 1 g (II′), (III),or (III′) Anhydrous Sodium Carbonate 0.1 g Ethanol (200 proof), USP 10mL Purified Water, USP 90 mL Aspartame 0.003 gTopical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of Formula (I), (I′), (II), (II′), (III), or (III′) is mixedwith 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mLof isopropyl myristate and 100 mL of purified alcohol USP. The resultinggel mixture is then incorporated into containers, such as tubes, whichare suitable for topical administration.

While preferred embodiments of the present disclosure have been shownand described herein, it will be obvious to those skilled in the artthat such embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments described herein may beemployed in practicing the invention. It is intended that the followingclaims define the scope of the invention and that methods and structureswithin the scope of these claims and their equivalents be coveredthereby.

What is claimed is:
 1. A compound having the structure of Formula (I):

wherein: R¹ is selected from:

R², R⁴, R¹⁰, R¹¹, R¹², and R¹³ are each independently —H, —CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH,—CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂C(O)OR²⁵, —CH₂CH₂C(O)OH,—CH₂CH₂C(O)OR²⁵, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂,—CH₂CH₂C(O)N(H)C(H)(CH₃)CO₂H, —CH₂CH₂C(O)N(H)C(H)(CO₂H)CH₂CO₂H,—CH₂NR²¹R²², —(CH₂)₂NR²¹R²², —(CH₂)₃NR²¹R²², —(CH₂)₄NR²¹R²²,—(CH₂)₄N(R²⁵)₃, —(CH₂)₄N(H)C(O)(2,3-dihydroxybenzene), optionallysubstituted C₁-C₈alkyl, optionally substituted C₁-C₈heteroalkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted—CH₂—C₃-C₈cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted heteroaryl,

R³ is methyl, ethyl, isopropyl, or cyclopropyl; R⁵ is H, methyl, ethyl,or —CH₂OH; or R⁵ and R²⁴ together with the boron atom form a 5- or6-membered boron containing ring; R⁶ is —CH₂C(═O)H, —B(OR²³)(OR²⁴), or

or R⁵ and R⁶ together with the carbon atom form

R^(x) is H, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆heteroalkyl, or optionally substituted C₃-C₈cycloalkyl; or R^(x)and R² together with the nitrogen atom form an optionally substitutednitrogen containing ring; R^(y) is H or methyl; or R^(y) and R⁵ togetherwith the nitrogen atom form an optionally substituted nitrogencontaining ring; R^(z) is —NR¹⁵R¹⁶, —CH₂—NR¹⁵R¹⁶, or —(CH₂)₂—NR¹⁵R¹⁶; R⁷is optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocycloalkyl, optionally substituted alkenyl,or a linear or branched alkyl chain of about 1-22 carbon atoms,optionally comprising within the alkyl chain or at an alkyl chainterminus an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted heterocycloalkyl, or an optionallysubstituted

wherein Z is a bond, O, S, NH, CH₂, NHCH₂, or C≡C; R⁸ is a bond, —O—,—N(R¹⁷)—, optionally substituted aryl, or optionally substitutedheteroaryl; R⁹ is —CH₂OH, —CH₂CH(CH₃)₂,

R¹⁵ and R¹⁶ are each independently H, or C₁-C₄alkyl; R¹⁷ is H, methyl,ethyl, isopropyl, or cyclopropyl; R¹⁸, R¹⁹, and R²⁰ are eachindependently H, or methyl; each R²¹ is independently H, or C₁-C₄alkyl;each R²² is independently H, C₁-C₄alkyl, —C(═NH)(NH₂), or —CH(═NH); R²³and R²⁴ are each independently H, or C₁-C₄alkyl; or R²³ and R²⁴ togetherwith the boron atom form an optionally substituted 5- or 6-memberedboron containing ring; each R²⁵ is independently C₁-C₆alkyl; R²⁶ is H,C₁-C₄alkyl, C₁-C₄alkoxy, —CH₂C(O)OR²⁵, or —OCH₂C(O)OR²⁵; n is 0 or 1; pis 0 or 1; and q is 0 or 1; or a pharmaceutically acceptable salt,solvate, or prodrug thereof.
 2. The compound of claim 1 wherein R¹ is


3. The compound of claim 2 wherein R⁸ is a bond.
 4. The compound ofclaim 3 wherein R², R⁴, R¹⁰, R¹¹, R¹², and R¹³ are each independently—H, —CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH,—CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂,—CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂,


5. The compound of claim 4 wherein R², R⁴, R¹⁰, R¹¹, R¹², and R¹³ areeach independently —H, —CH₃, —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃),—CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂,—(CH₂)₃NH₂, —(CH₂)₄NH₂, or


6. The compound of claim 5 wherein n is 1 and p is
 0. 7. The compound ofclaim 6 having the structure of Formula (Ib):

wherein R², R⁴, and R¹² are each independently —CH₂CH(CH₃)₂, —(CH₂)₃NH₂,or —(CH₂)₄NH₂.
 8. The compound of claim 1 wherein R¹ is


9. The compound of claim 8 wherein R², R⁴, R¹², and R¹³ are eachindependently —H, —CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃),—CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂CH₂C(O)OH,—CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂,—(CH₂)₄NH₂,


10. The compound of claim 9 wherein R², R⁴, R¹², and R¹³ are eachindependently —H, —CH₃, —CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)(CH₃),—CH₂CH₂C(O)OH, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂,—(CH₂)₃NH₂, —(CH₂)₄NH₂,


11. The compound of claim 10 wherein n is
 0. 12. The compound of claim11 wherein R⁸ is a bond.
 13. The compound of claim 12 having thestructure of Formula (Ic):

wherein R², R⁴, and R¹² are each independently —CH₂CH(CH₃)₂,—CH(OH)(CH₃), —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂,—(CH₂)₃NH₂, or —(CH₂)₄NH₂.
 14. The compound of claim 1 wherein R¹ is


15. The compound of claim 14 wherein R² and R⁴ are each independently—H, —CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —CH₂OH,—CH(OH)(CH₃), —CH₂CF₃, —CH₂C(O)OH, —CH₂CH₂C(O)OH, —CH₂C(O)NH₂,—CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂, —(CH₂)₄NH₂,


16. The compound of claim 15 wherein q is 1; and R⁸ is a bond.
 17. Thecompound of claim 16 having the structure of Formula (Id):

wherein R^(z) is NH₂; and R² and R⁴ are each independently —CH₂CH(CH₃)₂,—CH(OH)(CH₃), —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂NH₂, —(CH₂)₂NH₂,—(CH₂)₃NH₂, or —(CH₂)₄NH₂.
 18. A pharmaceutical composition comprising acompound of claim 1 and a pharmaceutically acceptable excipient.
 19. Amethod of treatment of a bacterial infection in a mammal, comprisingadministering an effective amount of a compound of claim 1 to the mammalat a frequency and for a duration sufficient to provide a beneficialeffect to the mammal.
 20. The method of claim 19, wherein the bacterialinfection is an infection involving Pseudomonas aeruginosa, Pseudomonasfluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes,Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia,Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii,Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi,Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri,Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes,Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens,Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteusvulgaris, Providencia alcalifaciens, Providencia rettgeri, Providenciastuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus,Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis,Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis,Bordetella parapertussis, Bordetella bronchiseptica, Haemophilusinfluenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus,Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurellamultocida, Pasteurella haemolytica, Branhamella catarrhalis,Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni,Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrioparahaemolyticus, Legionella pneumophila, Listeria monocytogenes,Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella,Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis,Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroidesovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroideseggerthii, Bacteroides splanchnicus, Clostridium difficile,Mycobacterium tuberculosis, Mycobacterium avium, Mycobacteriumintracellulare, Mycobacterium leprae, Corynebacterium diphtheriae,Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcusagalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcusfaecium, Staphylococcus aureus, Staphylococcus epidermidis,Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcushyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcushominis, or Staphylococcus saccharolyticus.
 21. The method of claim 19further comprising administering a second therapeutic agent.
 22. Thecompound of claim 13 wherein R⁶is


23. The compound of claim 13 wherein R⁶ is B(OH)₂.
 24. The compound ofclaim 22 or 23 wherein R⁷ is


25. The compound of claim 22 or 23 wherein R⁷ is